Tetracyclic compounds

ABSTRACT

This disclosure relates to new tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic [4,3-b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application U.S. Ser. No.13/679,873 filed Nov. 16, 2012, which is a continuation of applicationU.S. Ser. No. 12/259,234 filed Oct. 27, 2008, now issued as U.S. Pat.No. 8,338,408, which claims priority to U.S. Provisional PatentApplication No. 60/982,678 filed Oct. 25, 2007, U.S. Provisional PatentApplication No. 60/982,679 filed Oct. 25, 2007, U.S. Provisional PatentApplication No. 61/062,332 filed Jan. 25, 2008, U.S. Provisional PatentApplication No. 61/062,331 filed Jan. 25, 2008, U.S. Provisional PatentApplication No. 61/033,754 filed Mar. 4, 2008, U.S. Provisional PatentApplication No. 61/033,757 filed Mar. 4, 2008, and Russian PatentApplication No. 2007139634 filed Oct. 25, 2007, the disclosures of eachof which are incorporated herein by reference in their entireties.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

BACKGROUND OF THE INVENTION

Neurotransmitters such as histamine, serotonin, dopamine andnorepinephrine mediate a large number of processes in the centralnervous system (CNS) as well as outside the CNS. Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited to, Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barre syndrome, mild cognitiveimpairment, schizophrenia, anxiety, multiple sclerosis, stroke,traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases. Compounds that modulate these neurotransmitters maybe useful therapeutics.

Histamine receptors belong to the superfamily of G protein-coupled seventransmembrane proteins. G protein-coupled receptors constitute one ofthe major signal transduction systems in eukaryotic cells. Codingsequences for these receptors, in those regions believed to contributeto the agonist-antagonist binding site, are strongly conserved acrossmammalian species. Histamine receptors are found in most peripheraltissue and within the central nervous system. Compounds capable ofmodulating a histamine receptor may find use in therapy, e.g., histamineantagonists may find use as antihistamines.

Dimebon is a known anti-histamine drug that has also been characterizedas a neuroprotective agent useful to treat, inter alia,neurodegenerative diseases. Dimebon has been shown to inhibit the deathof brain cells (neurons) in preclinical models of Alzheimer's diseaseand Huntington's disease, making it a novel potential treatment forthese and other neurodegenerative diseases. In addition, dimebon hasbeen shown to improve the mitochondrial function of cells in the settingof cellular stress with very high potency. For example, dimebontreatment improved mitochondrial function and increased the number ofsurviving cells after treatment with the cell toxin ionomycin in a dosedependent fashion. Dimebon has also been shown to promote neuriteoutgrowth and neurogenesis, processes important in the formation of newand/or enhanced neuronal cell connections, and evidence of dimebon'spotential for use in additional diseases or conditions. See, e.g., U.S.Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos.PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077,PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645,PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626,PCT/US2008/009357, PCT/US2007/024623 and PCT/US2008/008121. Allreferences disclosed herein and throughout, such as publications,patents, patent applications and published patent applications, areincorporated herein by reference in their entireties.

Although dimebon holds great promise as a drug for the treatment ofneurodegenerative diseases and/or diseases in which neurite outgrowthand/or neurogenesis may be implicated in therapy, there remains a needfor new and alternative therapies for the treatment of such diseases orconditions. In addition, there remains a need for new and alternativeantihistamine drugs, preferably ones in which side-effects such asdrowsiness are reduced or eliminated. Compounds that exhibit enhancedand/or more desirable properties than dimebon (e.g., superior safety andefficacy) may find particular use in the treatment of at least thoseindications for which dimebon is believed to be advantageous. Further,compounds that exhibit a different therapeutic profile than dimebon asdetermined, e.g. by in vitro and/or in vivo assays, may find use inadditional diseases and conditions.

BRIEF SUMMARY OF THE INVENTION

Numerous compounds have been synthesized and tested in biochemical andcell-based assays as well as in in vivo studies.

Tetracyclic compounds of the general Formula (I) are described as newhistamine receptor modulators. Other compounds are also detailed herein.Compositions comprising the compounds are provided, as are kitscomprising the compound as well as methods of using and making thecompounds. Other tetracyclic compounds are also provided. Compounds ofthe invention may also find use in treating neurodegenerative diseases.Compounds of the invention may also find use in treating diseases and/orconditions in which modulation of aminergic G protein-coupled receptorsand/or neurite outgrowth may be implicated in therapy. Compoundsdisclosed herein may find use the methods disclosed herein, includinguse in treating, preventing, delaying the onset and/or delaying thedevelopment of a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder in anindividual in need thereof, such as humans.

In one variation, provided are compounds of the Formula (I):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano or nitro or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

X¹ is N or CH;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl or is taken together with the carbon to whichit is attached and a geminal R^(8(a-f)) to form a cycloalkyl moiety or acarbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl moiety;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or a substituted or an unsubstitutedheterocyclyl;

provided that: (i) when X¹ is N the compound is other than a compound inTable 1 or salt thereof; (ii) the compound is other than any ofcompounds 229H, 230, 241, 255, 256, 262 and 274 or a salt thereof; and(iii) the compound is other than those compounds listed in U.S. Pat.Nos. 6,187,785, 7,071,206, 3,409,628 and 6,849,640 or in PCT PublicationNos. WO 2005/055951, WO 2007/041697 and WO 2007/087425. In anothervariation, the compounds of the invention, pharmaceutical compositionsthereof, isolated forms thereof and methods of using and administeringthe compounds detailed herein, encompass any of the compounds of Formula(I), including those listed in Table 1 or a salt thereof and compounds229H, 230, 241, 255, 256, 262 and 274 or a salt thereof. In onevariation, the compound is of the formula (I) wherein R⁴ is other than asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, an aryloxy and an aralkyl. In one variation the compound isof the formula (I) wherein R⁴ is other than a substituted orunsubstituted aryl. In a further variation, the compound is of Formula(I) where at least one of X⁷-X⁹ is C—R⁴ and R⁴ is other than H. In onevariation, the compounds listed in any of PCT publication numbers WO2008/123800, WO 2008/123796, WO 2008/115098 and WO 2008/060190 areexcluded from any compound formulae detailed herein and suchpublications are incorporated herein by reference in their entiretiesand specifically with respect to the compound species detailed therein.In one variation, the compounds listed in any of PCT publication numbersWO 2008/123800, WO 2008/123796, WO 2008/115098 and WO 2008/060190 areincluded in any compound formulae detailed herein and may find use inthe methods provided. In another variation, the compound is of theformula (I) further provided that when Q is a substituted orunsubstituted heteroaryl, it is other than a thiazole, triazole, oroxadiazole. However, in another variation, the compound is of theformula (I) and includes compounds in which Q is a thiazole, triazole,or oxadiazole. In still another variation, the compound is of theformula (I) further provided that the compound is other than a compoundof formula (G). However, in another variation, the compound is of theformula (I) and includes compounds that conform to the formula (G).

TABLE 1 Compound No. Compound Name  1x 1H-Pyrido[4,3-b]indole,5-[(2,4-dimethylphenyl)methyl]-2,3,4,5-tetrahydro-2,8- dimethyl-  2xPiperidine, 1-[[5-[(2,6-difluorophenyl)methyl]-2,3,4,5-tetrahydro-2-(1-methylethyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methoxy-  3x2H-Pyrido[4,3-b]indole-2-carboxylic acid,1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5-[(2-methyl-4-thiazolyl)methyl]-,1,1-dimethylethylester  4x Piperidine,1-[[2-cyclopentyl-2,3,4,5-tetrahydro-5-[(2-methyl-4-thiazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  5x Piperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-[(2-methyl-4-thiazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-  6x2H-Pyrido[4,3-b]indole-2-carboxylic acid,5-[[4-(ethylsulfonyl)phenyl]methyl]-1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-,1,1-dimethylethyl ester  7x 2H-Pyrido[4,3-b]indole-2-carboxylic acid,1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5-[[4-(methylsulfonyl)phenyl]methyl]-,1,1-dimethylethylester  8x Piperidine, 1-[[2-cyclopentyl-2,3,4,5-tetrahydro-5-[[4-(methylsulfonyl)phenyl]methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl- 9x Piperidine, 4-methyl-1-[[2,3,4,5-tetrahydro-5-[[4-(methylsulfonyl)phenyl]methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]- 10x 2H-Pyrido[4,3-b]indole-2-carboxylic acid,1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5-[[4-(methylthio)phenyl]methyl]-,1,1-dimethylethylester  11x Piperidine, 1-[[2-cyclopentyl-2,3,4,5-tetrahydro-5-[[4-(methylthio)phenyl]methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl- 12x Piperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-[[4-(methylthio)phenyl]methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-  13x 2H-Pyrido[4,3-b]indole,5-p-chlorobenzyl-1,3,4,5-tetrahydro-2-methyl-  14x2H-Pyrido[4,3-b]indole,7-chloro-5-p-chlorobenzyl-1,3,4,5-tetrahydro-2-methyl-  15x2H-Pyrido[4,3-b]indole,8-chloro-5-p-chlorobenzyl-1,3,4,5-tetrahydro-2-methyl-  16x1H-Pyrido[4,3-b]indole,2-(cyclobutylcarbonyl)-5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-  17x2H-Pyrido[4,3-b]indole-2-carboxylic acid,5-[(4-ethoxyphenyl)methyl]-1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-,1,1-dimethylethyl ester 18x Piperidine,1-[[2-(3,4-dihydro-2H-pyrrol-2-yl)-5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  19xPiperidine,1-[[2-(cyclopropylmethyl)-5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  20xPiperidine,1-[[2-cyclobutyl-5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  21x Piperidine,1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  22x Piperidine,1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-2-(1-methylethyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methoxy-  23x Piperidine,1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-2-(2-methylpropyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  24xPiperidine,1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-2-(2-pyrimidinyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  25x Piperidine,1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-2-(3,4,5,6-tetrahydro-2-pyridinyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl- 26x Piperidine,1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  27xPiperidine,1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-2-propyl-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  28x Piperidine,4-ethoxy-1-[[5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-2-(1-methylethyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-  29x1H-Pyrido[4,3-b]indole,8-fluoro-5-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-2-[2-(2-pyridinyl)ethyl]-  30x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-(4-hydroxybenzoyl)-5-[(4- hydroxyphenyl)methyl]- 31x 2H-Pyrido[4,3-b]indole,8-chloro-1,3,4,5-tetrahydro-5-p-methoxybenzyl-2- methyl-  32xPiperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-[(4-methoxyphenyl)methyl]-2-(1-methylethyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-  33x2-Furancarboxylic acid,5-[[2-cyclopentyl-1,2,3,4-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5H-pyrido[4,3-b]indol-5-yl]methyl]-, methyl ester 34x 2-Furancarboxylic acid,5-[[2-cyclopentyl-1,2,3,4-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5H-pyrido[4,3-b]indol-5-yl]methyl]-  35x2H-Pyrido[4,3-b] indole-2-carboxylic acid,1,3,4,5-tetrahydro-5-[(5-methyl-4-isoxazolyl)methyl]-8-[(4-methyl-1-piperidinyl)carbonyl]-,1,1-dimethylethylester  36x Piperidine,1-[[2-cyclopentyl-2,3,4,5-tetrahydro-5-[(5-methyl-4-isoxazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  37xPiperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-[(5-methyl-4-isoxazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-  38x Piperidine,1-[[5-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-2,3,4,5-tetrahydro-2-(1-methylethyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methoxy-  39x1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[1-(6-methyl-2- pyridinyl)ethyl]- 40x 1H-Pyrido[4,3-b]indole,8-bromo-2,3,4,5-tetrahydro-2-methyl-5-[1-(6-methyl-3- pyridinyl)ethyl]- 41x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[1-(6-methyl-3- pyridinyl)ethyl]- 42x 2H-Pyrido[4,3-b]indole-2-carboxylic acid,5-(cyclobutylmethyl)-1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-, 1,1-dimethylethylester  43x Piperidine,1-[[5-(cyclobutylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  44x Piperidine,1-[[5-(cyclobutylmethyl)-2-cyclopentyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  45x1H-Pyrido[4,3-b]indol-1-one,5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-  46x 1H-Pyrido[4,3-b]indol-1-one,5-(cyclopentylmethyl)-6-fluoro-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-  47x2H-Pyrido[4,3-b]indole-2-carboxylic acid, 5-(cyclopropylmethyl)-1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-, 1,1-dimethylethylester  48x 2H-Pyrido[4,3-b]indole-2-carboxylic acid,5-(cyclopropylmethyl)-9-[[(3,5-dichloro-4-pyridinyl)amino]carbonyl]-1,3,4,5-tetrahydro-6-methoxy-,1,1-dimethylethyl ester  49x Piperidine,1-[[2-cyclopentyl-5-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  50x Piperidine,1-[[5-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-  51x 1H-Pyrido[4,3-b]indol-1-one,2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-(phenylmethyl)-  52x 1H-Pyrido[4,3-b]indol-8-ol,2,3,4,5-tetrahydro-5-(phenylmethyl)-  53x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-1,1,3,3-tetramethyl-5-(phenylmethyl)-  54x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2-(3-phenoxypropyl)-5-(phenylmethyl)-  55x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,5-bis(phenylmethyl)-  56x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,8-dimethyl-5-(phenylmethyl)-  57x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2-methyl-5-(phenylmethyl)- 58x 1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-5-(phenylmethyl)-  59x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-8-(phenylmethoxy)-5-(phenylmethyl)-  60x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-8-methyl-2,5-bis(phenylmethyl)-  61x1H-Pyrido[4,3-b]indole, 2-acetyl-2,3,4,5-tetrahydro-5-(phenylmethyl)- 62x 1H-Pyrido[4,3-b]indole,2-butyl-2,3,4,5-tetrahydro-5-(phenyltmethyl)-  65x1H-Pyrido[4,3-b]indole, 5-benzyl-2,3,4,5-tetrahydro-2-phenethyl-  66x1H-Pyrido[4,3-b]indole,9-bromo-2,3,4,5-tetrahydro-2-methyl-5-(phenylmethyl)-  67x1H-Pyrido[4,3-b]indole,9-chloro-2,3,4,5-tetrahydro-2-methyl-5-(phenylmethyl)-  68x1H-Pyrido[4,3-b]indole-1,3(2H)-dione,4,5-dihydro-5-(phenylmethyl)-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-  69x1H-Pyrido[4,3-b]indole-1,3(2H)-dione, 4,5-dihydro-8-methoxy-2-methyl-5-(phenylmethyl)-  70x 1H-Pyrido[4,3-b]indole-1-carbonitrile,2,3,4,5-tetrahydro-2-methyl-5- (phenylmethyl)-  71x1H-Pyrido[4,3-b]indole-6-carboxylic acid, 2-acetyl-2,3,4,5-tetrahydro-5-(phenylmethyl)-  72x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3- pyridyl)ethyl]-, N-oxide 73x 1H-Pyrido[4,3-b]indole-9-carboxamide,N-(3,5-dichloro-4-pyridinyl)-2,3,4,5-tetrahydro-6-methoxy-2-methyl-5-(phenylmethyl)-  74x1H-Pyrido[4,3-b]indole-9-carboxamide,N-(3,5-dichloro-4-pyridinyl)-2,3,4,5-tetrahydro-6-methoxy-5-(phenylmethyl)-  77x 2,4(1H,3H)-Quinazolinedione,3-[2-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-  78x 2,4(1H,3H)-Quinazolinedione,3-[3-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]propyl]-  79x 2H-Pyrido[4,3-b]indole,5-benzyl-1,3,4,5-tetrahydro-2,4-dimethyl-  80x 2H-Pyrido[4,3-b]indole,5-benzyl-1,3,4,5-tetrahydro-7-methoxy-2-methyl-  81x2H-Pyrido[4,3-b]indole, 5-benzyl-1,3,4,5-tetrahydro-8-methoxy-2-methyl- 82x 2H-Pyrido[4,3-b]indole,5-benzyl-7-bromo-1,3,4,5-tetrahydro-2-methyl-  83x2H-Pyrido[4,3-b]indole, 5-benzyl-7-chloro-1,3,4,5-tetrahydro-2-methyl- 84x 2H-Pyrido[4,3-b]indole,5-benzyl-8-chloro-1,3,4,5-tetrahydro-2-methyl-  85x2H-Pyrido[4,3-b]indole, 5-benzyl-8-ethoxy-1,3,4,5-tetrahydro-2-methyl- 88x 2H-Pyrido[4,3-b]indole-2-carbonitrile,1,3,4,5-tetrahydro-5-(phenylmethyl)-  89x2H-Pyrido[4,3-b]indole-2-carboxylic acid,1,3,4,5-tetrahydro-5-(phenylmethyl)-, ethyl ester  90x2H-Pyrido[4,3-b]indole-2-carboxylic acid,1,3,4,5-tetrahydro-8-(phenylmethoxy)- 5-(phenylmethyl)-, ethyl ester 91x 2H-Pyrido[4,3-b]indole-2-carboxylic acid, 9-[[(3,5-dichloro-4-pyridinyl)amino]carbonyl]-1,3,4,5-tetrahydro-6-methoxy-5-(phenylmethyl)-,1,1-dimethylethyl ester  92x 2H-Pyrido[4,3-b]indole-2-ethanol,1,3,4,5-tetrahydro-5-(phenylmethyl)-  93x4H-Pyrido[1,2-a]pyrimidin-4-one,2-(phenylmethyl)-3-[2-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-  94x4H-Pyrido[1,2-a]pyrimidin-4-one, 2-methyl-3-[2-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-  95x4H-Pyrido[1,2-a]pyrimidin-4-one,2-methyl-3-[2-[1,3,4,5-tetrahydro-8-hydroxy-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-  96x4H-Pyrido[1,2-a]pyrimidin-4-one, 2-phenyl-3-[2-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-  97x4H-Pyrido[1,2-a]pyrimidin-4-one,6,7,8,9-tetrahydro-2-methyl-3-[2-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-  98x4H-Pyrido[1,2-a]pyrimidin-4-one,6,7,8,9-tetrahydro-2-methyl-3-[2-[1,3,4,5-tetrahydro-8-hydroxy-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-100x 5H-Thiazolo[3,2-a]pyrimidin-5-one,2,3-dihydro-7-methyl-6-[2-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]- 101x5H-Thiazolo[3,2-a]pyrimidin-5-one, 7-methyl-6-[2-[1,3,4,5-tetrahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]- 102x5H-Thiazolo[3,2-a]pyrimidin-5-one, 7-methyl-6-[2-[1,3,4,5-tetrahydro-8-hydroxy-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]- 103xPiperidine,4-methyl-1-[[2,3,4,5-tetrahydro-2-(1-methylethyl)-5-(phenylmethyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]- 104x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-(2-pyridinylmethyl)- 105x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[1-(2-pyridinyl)ethyl]- 106x1H-Pyrido[4,3-b]indole, 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-pyridinylmethyl)- 107x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[1-(2- pyridinyl)ethyl]- 109x2H-Pyrido[4,3-b]indole-2-carboxylic acid,1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5-(2-pyridinylmethyl)-, 1,1-dimethylethyl ester110x Piperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-(2-pyridinylmethyl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]- 111x Piperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-(2-pyridinylmethyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrido[4,3-b]indol-8-yl]carbonyl]- 113x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2,7,8-trimethyl-5-[1-(3-pyridinyl)ethyl]- 114x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,8,9-trimethyl-5-[1-(3- pyridinyl)ethyl]- 115x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,8-dimethyl-5-[1-(3-pyridinyl)ethyl]- 116x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[1-(3-pyridinyl)ethyl]- 117x 1H-Pyrido[4,3-b]indole,8-bromo-2,3,4,5-tetrahydro-2-methyl-5-[1-(3- pyridinyl)ethyl]- 118x1H-Pyrido[4,3-b]indole, 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(3-pyridinylmethyl)- 119x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[1-(3- pyridinyl)ethyl]- 120x1H-Pyrido[4,3-b]indole, 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(4-pyridinylmethyl)- 121x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[1-(4- pyridinyl)ethyl]- 122x2H-Pyrido[4,3-b]indole-2-carboxylic acid,1,3,4,5-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5-[(tetrahydro-2H-pyran-4-yl)methyl]-,1,1-dimethylethylester 123x Piperidine,1-[[2-(cyclopropylmethyl)-2,3,4,5-tetrahydro-5-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl- 124xPiperidine, 4-methyl-1-[[2,3,4,5-tetrahydro-5-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]- 125x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2-methyl-5-[2-(2-methyl-3-pyridinyl)ethyl]- 126x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl]- 127x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-5-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-(phenylmethyl)- 128x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-methyl- 129x 1H-Pyrido[4,3-b]indole,2-acetyl-2,3,4,5-tetrahydro-5-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- 130x 1H-Pyrido[4,3-b]indole,2-benzoyl-2,3,4,5-tetrahydro-5-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- 131x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,7,8-trimethyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-132x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,7-dimethyl-5-[2-(6-methyl-3- pyridinyl)ethyl]- 133x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,8,9-trimethyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-134x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3- pyridinyl)ethyl]- 135x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2-isobutyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 136x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-isobutyl-8-methoxy-5-[2-(6-methyl-3-pyridinyl)ethyl]- 137x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-isobutyl-8-methyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 138x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-isopentyl-5-[2-(6-methyl-3- pyridinyl)ethyl]- 139x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-isopentyl-8-methyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 140x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]- 141x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-7-(trifluoromethyl)- 142x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-(6-methyl-3-pyridinyl)ethyl]- 143x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-(6-methyl-3-pyridinyl)ethyl]-2- (phenylmethyl)-144x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-(6-methyl-3-pyridinyl)ethyl]-2- pentyl- 145x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-(6-methyl-3-pyridinyl)ethyl]-2- phenyl- 146x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-(6-methyl-3-pyridinyl)ethyl]-2- propyl- 148x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 149x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-8-methoxy-5-[2-(6-methyl-3-pyridinyl)ethyl]-2-propyl- 150x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-8-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]- 151x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-8-methyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-2-(phenylmethyl)- 152x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-8-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-2-propyl-155x 1H-Pyrido[4,3-b]indole,2-benzyl-8-chloro-2,3,4,5-tetrahydro-5-[2-(6-methyl-3- pyridinyl)ethyl]-156x 1H-Pyrido[4,3-b]indole,2-butyl-2,3,4,5-tetrahydro-4-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-157x 1H-Pyrido[4,3-b]indole,2-butyl-2,3,4,5-tetrahydro-5-[2-(6-methyl-3- pyridinyl)ethyl]- 158x1H-Pyrido[4,3-b]indole,2-butyl-2,3,4,5-tetrahydro-8-methoxy-5-[2-(6-methyl-3- pyridinyl)ethyl]-159x 1H-Pyrido[4,3-b]indole,2-butyl-2,3,4,5-tetrahydro-8-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-160x 1H-Pyrido[4,3-b]indole,2-cyclohexyl-2,3,4,5-tetrahydro-5-[2-(6-methyl-3- pyridinyl)ethyl]- 161x1H-Pyrido[4,3-b]indole, 2-ethyl-2,3,4,5-tetrahydro-5-[2-(6-methyl-3-pyridinyl)ethyl]- 162x 1H-Pyrido[4,3-b]indole,2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-163x 1H-Pyrido[4,3-b]indole,2-heptyl-2,3,4,5-tetrahydro-5-[2-(6-methyl-3- pyridinyl)ethyl]- 164x1H-Pyrido[4,3-b]indole,2-heptyl-2,3,4,5-tetrahydro-8-methoxy-5-[2-(6-methyl-3-pyridinyl)ethyl]- 165x 1H-Pyrido[4,3-b]indole,2-heptyl-2,3,4,5-tetrahydro-8-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-166x 1H-Pyrido[4,3-b]indole,2-sec-butyl-2,3,4,5-tetrahydro-5-[2-(6-methyl-3- pyridinyl)ethyl]- 167x1H-Pyrido[4,3-b]indole,2-sec-butyl-2,3,4,5-tetrahydro-8-methyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 168x 1H-Pyrido[4,3-b]indole,7,8-dichloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 169x 1H-Pyrido[4,3-b]indole,7-chloro-2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 170x 1H-Pyrido[4,3-b]indole,7-chloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-171x 1H-Pyrido[4,3-b]indole,8-bromo-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-172x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2,6-dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 173x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2,7-dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]- 174x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-175x 1H-Pyrido[4,3-b]indole,8-ethyl-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3- pyridinyl)ethyl]-176x 1H-Pyrido[4,3-b]indole,5-[2-(hexahydro-1H-azepin-1-yl)ethyl]-2,3,4,5- tetrahydro-2,8-dimethyl-177x 2H-Pyrido[4,3-b]indole, 1,3,4,5-tetrahydro-2-methyl-5-phenethyl-178x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(1-piperidinyl)ethyl]- 179x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-(2-piperidinoethyl)- 180x1H-Pyrido[4,3-b]indole,1-butyl-2,3,4,5-tetrahydro-5-[2-(2-pyridinyl)ethyl]- 181x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethyl]- 182x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-propyl-5-[2-(2-pyridinyl)ethyl]- 183x1H-Pyrido[4,3-b]indole,2-butyl-2,3,4,5-tetrahydro-5-[2-(2-pyridinyl)ethyl]- 184x1H-Pyrido[4,3-b]indole, 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethyl]- 185x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,6-dimethyl-5-[2-(4-pyridinyl)ethyl]- 186x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2,7,8-trimethyl-5-[2-(4-pyridinyl)ethyl]- 187x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,7-dimethyl-5-[2-(4-pyridinyl)ethyl]- 188x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2,8,9-trimethyl-5-[2-(4-pyridinyl)ethyl]- 189x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(4-pyridinyl)ethyl]- 190x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethyl]- 191x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethyl]-8-(trifluoromethyl)- 192x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-propyl-5-[2-(4-pyridinyl)ethyl]- 193x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[2-(4-pyridinyl)ethyl]- 194x 1H-Pyrido[4,3-b]indole,2-benzoyl-8-chloro-2,3,4,5-tetrahydro-5-[2-(4- pyridinyl)ethyl]- 195x1H-Pyrido[4,3-b]indole,2-butyl-2,3,4,5-tetrahydro-5-[2-(4-pyridinyl)ethyl]- 196x1H-Pyrido[4,3-b]indole, 2-butyl-2,3,4,5-tetrahydro-8-methyl-5-[2-(4-pyridinyl)ethyl]- 197x 1H-Pyrido[4,3-b]indole,7-chloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(4- pyridinyl)ethyl]- 198x1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-(2-phenylethyl)-5-[2-(4- pyridinyl)ethyl]-199x 1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(4- pyridinyl)ethyl]- 200x1H-Pyrido[4,3-b]indole,8-chloro-2,3,4,5-tetrahydro-5-[2-(4-pyridinyl)ethyl]- 201x1H-Pyrido[4,3-b]indole-8-carboxylic acid,2,3,4,5-tetrahydro-2-methyl-5-[2-(4- pyridinyl)ethyl]- 202x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-2-methyl-5-[3-(4-morpholinyl)propyl]- 203x 1H-Pyrido[4,3-b]indole-8-methanol,2,3,4,5-tetrahydro-2-methyl-5-[2-(4- pyridinyl)ethyl]- 204x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[2-(1-pyrrolidinyl)ethyl]- 205x1H-Pyrido[4,3-b]indole, 2,3,4,5-tetrahydro-5-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]- 206x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2-(phenylmethyl)- 207x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2-methyl- 208x 1H-Pyrido[4,3-b]indole,2-acetyl-2,3,4,5-tetrahydro-5-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]- 209x 1H-Pyrido[4,3-b]indole,2-benzoyl-2,3,4,5-tetrahydro-5-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]- 210x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[3-[4-(phenylmethyl)-1-piperazinyl]propyl]- 211x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[3-(4-methyl-1- piperazinyl)propyl]- 212x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[3-(4-methyl-1-piperazinyl)propyl]-2-(2-phenylethyl)- 213x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[3-(4-methyl-1-piperazinyl)propyl]-2-(phenylmethyl)- 214x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[3-(4-methyl-1-piperazinyl)propyl]- 216x 1H-Pyrido[4,3-b]indol-1-one,2,3,4,5-tetrahydro-5-(phenylmethyl)- 217x 1H-Pyrido[4,3-b]indol-1-one,5-(cyclopentylmethyl)-2,3,4,5-tetrahydro- 218x1H-Pyrido[4,3-b]indol-1-one,5-(cyclopentylmethyl)-6-fluoro-2,3,4,5-tetrahydro- 219x1H-Pyrido[4,3-b]indole, 2-benzoyl-2,3,4,5-tetrahydro-8-methoxy-5-(2-pyridinylcarbonyl)- 220x 1H-Pyrido[4,3-b]indole,5-(4-chlorobenzoyl)-2,3,4,5-tetrahydro-8-methoxy-2- methyl- 221x1-Propanone,1-(2-chloro-10H-phenothiazin-10-yl)-3-(1,2,3,4-tetrahydro-2-methyl-5H-pyrido[4,3-b]indol-5-yl)- 222x Ethanone,1-(ethyl-1-piperazinyl)-2-[1,2,3,4-tetrahydro-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]- 223x Ethanone,1-(4-methyl-1-piperazinyl)-2-[1,2,3,4-tetrahydro-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]- 224x Ethanone,1-(4-methyl-1-piperazinyl)-2-[1,2,3,4-tetrahydro-8-methyl-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]- 225x Ethanone,1-[4-(2-methoxyphenyl)-1-piperazinyl]-2-[1,2,3,4-tetrahydro-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]- 226x Ethanone,1-[4-(diphenylmethyl)-1-piperazinyl]-2-[1,2,3,4-tetrahydro-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]- 227x Ethanone,1-[4-(phenylmethyl)-1-piperazinyl]-2-[1,2,3,4-tetrahydro-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]- 228x Ethanone,2-[1,2,3,4-tetrahydro-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]-1-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]- 229x Ethanone,2-[8-ethyl-1,2,3,4-tetrahydro-2-(1-methylethyl)-5H-pyrido[4,3-b]indol-5-yl]-1-(4-methyl-1-piperazinyl)- 230x Methanone,(4-fluorophenyl)[2-[2-[3-fluoro-5-(tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy]ethyl]-1,2,3,4-tetrahydro-7-methoxy-5H-pyrido[4,3-b]indol-5-yl]-231x Methanone, (4-methyl-1-piperidinyl)[2,3,4,5-tetrahydro-5-(4-morpholinylcarbonyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-pyrido[4,3-b]indol-8-yl]-232x Methanone,[1,1′-biphenyl]-4-yl(1,2,3,4-tetrahydro-8-methoxy-2-methyl-5H-pyrido[4,3-b]indol-5-yl)- 233x1-(4-benzhydrylpiperazin-1-yl)-2-(7-aza-2-isopropyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanone 234x1-(4-benzylpiperazin-1-yl)-2-(7-aza-2-isopropyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanone 235x1-(4-ethylpiperazin-1-yl)-2-(7-aza-2-isopropyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanone 236x 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-propyl-5-(phenylmethyl)- 237x1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-5-[2-(2-methyl-3-pyridinyl)ethyl]- 238x Methanone,[1-(difluoromethyl)-1H-pyrazol-5-yl](1,2,3,4-tetrahydro-2,8-dimethyl-5H-pyrido[4,3-b]indol-5-yl)- 239x Methanone,[2-(3,4-dihydro-2H-pyrrol-5-yl)-5-[(4-ethoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl](4-methyl-1-piperidinyl)- 243x2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 244x8-fluoro-2-methyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole245x2-methyl-5-phenethyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 246x6-fluoro-2-methyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole247x2-methyl-5-phenethyl-6-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 248x2-methyl-5-(2-(pyridin-3-yl)ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole249x2,8-dimethyl-5-(2-(pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole250x2,8-dimethyl-5-(2-(pyridin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole251x2,8-dimethyl-5-(2-(pyrazin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole252x8-fluoro-2-methyl-5-(2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 253x8-fluoro-2-methyl-5-(2-pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 254x8-fluoro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 255x8-fluoro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 256x2-methyl-5-(2-(pyridin-3-yl)ethyl)-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 257x2-methyl-5-(2-(pyridin-3-yl)ethyl)-6-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 258x2-tert-butyl-8-methyl-5-(2-(pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 259x ethyl5-(pyridin-4-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate 260x ethyl5-(pyridin-3-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate 261x ethyl5-(pyridin-2-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate 262x5-benzyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid 263x5-(4-fluorobenzyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid 264x2-methyl-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid 265x2-methyl-5-(pyridin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid 266x5-(4-fluorobenzyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole267x2-methyl-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole268x2-methyl-5-(pyridin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole269x5-benzyl-8-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole270x8-fluoro-2-methyl-5-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 271x8-fluoro-2-methyl-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 272x8-fluoro-2-methyl-5-(pyridin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 273x5-(4-fluorobenzyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole274x5-benzyl-2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole275x2-methyl-5-(pyridin-3-ylmethyl)-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 276x2-methyl-5-(pyridin-4-ylmethyl)-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 277x5-benzyl-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole278x2-methyl-5-(pyridin-3-ylmethyl)-6-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 279x8-fluoro-2-methyl-5-(3-methylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole280x8-fluoro-2-methyl-5-(thiophen-2-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 281x2,8-dimethyl-5-((1,2,5,6-tetrahydropyridin-3-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 282x2-benzyl-5-(3-chlorobenzyl)-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole283x ethyl2-(5-benzyl-6-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)acetate284x ethyl2-(5-(4-fluorobenzyl)-6-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)acetate 285x ethyl3-(8-fluoro-5-(4-fluorobenzyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)propanoate 286x ethyl3-(5-(pyridin-3-ylmethyl)-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)propanoate 287x ethyl4-(8-fluoro-5-(pyridin-3-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)butanoate 288x ethyl4-(5-(pyridin-4-ylmethyl)-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)butanoate 289x2-(5-benzyl-6-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)aceticacid 290x3-(8-fluoro-5-(4-fluorobenzyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)propanoic acid 291x3-(5-(pyridin-3-ylmethyl)-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)propanoic acid 292x4-(8-fluoro-5-(pyridin-3-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)butanoic acid 293x ethyl4-((8-fluoro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)methyl)benzoate 294x5-benzyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid 295x2-methyl-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid

TABLE 1A Compound No. Compound Name 240x1H-Pyrido[4,3-b]indole-6-carboxylic acid, 2-acetyl-2,3,4,5-tetrahydro-5-(phenylmethyl)-, phenylmethyl ester 241x1H-Pyrido[4,3-b]indole-8-carboxylic acid,2,3,4,5-tetrahydro-2-methyl-5-[2-(4- pyridinyl)ethyl]-, ethyl ester 296xethyl5-benzyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate297x ethyl5-(4-fluorobenzyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 298x ethyl2-methyl-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 299x ethyl2-methyl-5-(pyridin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 300x ethyl5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 301xethyl5-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate302x ethyl5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 303x ethyl5-benzyl-2-(2-(pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 304x ethyl5-(4-fluorobenzyl)-2-(2-(pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 305x ethyl2-(4-fluorobenzyl)-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 306x ethyl2-benzyl-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate 307x diethyl5-(pyridin-3-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate 308x diethyl5-benzyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate 309xdiethyl 5-(4-fluorobenzyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate 310x ethyl5-(4-fluorobenzyl)-2-(2-(pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxylate 311x ethyl5-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxylate312x ethyl5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxylate 313x ethyl5-(pyridin-5-ylmethyl)-2,3,4,5,-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxylate 314x ethyl5-(pyridin-4-ylmethyl)-2-(thiophen-2-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxylate 315x ethyl2-benzyl-5-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxylate 316x 2-tert-butyl 6-ethyl5-(4-fluorobenzyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2,6(5H)-dicarboxylate 317x 2-tert-butyl 6-ethyl5-(pyridin-4-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2,6(5H)-dicarboxylate 318x 2-tert-butyl 6-ethyl5-(pyridin-3-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2,6(5H)-dicarboxylate

In one variation, the compound is of the formula (I) wherein thecompound further is a type 1 compound. In another variation, thecompound is of the formula (I) wherein the compound further is a type 2compound. In yet another variation, the compound is of the formula (I)wherein the compound further is a type 3 compound. In a furthervariation, the compound is of the formula (I) wherein the compoundfurther is a type 4 compound.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. The invention also includesany or all of the stereochemical forms, including any enantiomeric ordiasteriomeric forms, and any tautomers or other forms of the compoundsdescribed. Unless stereochemistry is explicitly indicated in a chemicalstructure or name, the structure or name is intended to embrace allpossible stereoisomers of a compound depicted. In addition, where aspecific stereochemical form is depicted, it is understood that otherstereochemical forms are also embraced by the invention. All forms ofthe compounds are also embraced by the invention, such as crystalline ornon-crystalline forms of the compounds. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical formthereof. Compositions comprising a mixture of compounds of the inventionin any ratio are also embraced by the invention, including mixtures oftwo or more stereochemical forms of a compound of the invention in anyratio, such that racemic, non-racemic, enantioenriched and scalemicmixtures of a compound are embraced.

In one aspect, compounds of the invention are used to treat, prevent,delay the onset and/or delay the development of any one or more of thefollowing: cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders inindividuals in need thereof, such as humans. In one variation, compoundsof the invention are used to treat, prevent, delay the onset and/ordelay the development of diseases or conditions for which the modulationof an aminergic G protein-coupled receptor is believed to be or isbeneficial. In one variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of any oneor more of diseases or conditions for which neurite outgrowth and/orneurogenesis and/or neurotrophic effects are believed to be or arebeneficial. In another variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of diseasesor conditions for which the modulation of an aminergic G protein-coupledreceptor and neurite outgrowth and/or neurogenesis and/or neurotrophiceffects are believed to be or are beneficial. In one variation, thedisease or condition is a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder.

In another aspect, compounds of the invention are used to improvecognitive function and/or reduce psychotic effects in an individual,comprising administering to an individual in need thereof an amount of acompound described herein or a pharmaceutically acceptable salt thereofeffective to improve cognitive function and/or reduce psychotic effects.

In a further aspect, compounds of the invention are used to stimulateneurite outgrowth and/or promote neurogenesis and/or enhanceneurotrophic effects in an individual comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to stimulate neuriteoutgrowth and/or to promote neurogenesis and/or to enhance neurotrophiceffects. Synapse loss is associated with a variety of neurodegenerativediseases and conditions including Alzheimer's disease, Huntington'sdisease, stroke, head trauma and spinal cord injury. Compounds of theinvention that stimulate neurite outgrowth may have a benefit in thesesettings.

In another aspect, compounds described herein are used to modulate anaminergic G protein-coupled receptor comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor. In one variation, a compound ofthe invention modulates at least one of the following receptors:adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g.,D2L) and histamine receptor (e.g., H1, H2 and/or H3). In anothervariation, at least two of the following receptors are modulated:adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g.,D2L) and histamine receptor (e.g., H1, H2 and/or H3). In anothervariation, at least three of the following receptors are modulated:adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g.,D2L) and histamine receptor (e.g., H1, H2 and/or H3). In anothervariation, each of the following receptors are modulated: adrenergicreceptor (e.g., α1D, α2A and/or α2B), serotonin receptor (e.g., 5-HT2A,5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g., D2L) and histaminereceptor (e.g., H1, H2 and/or H3). In another variation, at least one ofthe following receptors is modulated: α1D, α2A, α2B, 5-HT2A, 5-HT2C,5-HT6, 5-HT7, D2L, H1, H2 and H3. In another variation, at least two orthree or four or five or six or seven or eight or nine or ten or elevenof the following receptors are modulated: α1D, α2A, α2B, 5-HT2A, 5-HT2C,5-HT6, 5-HT7, D2L, H1, H2 and H3. In a particular variation, at leastdopamine receptor D2L is modulated. In another particular variation, atleast dopamine receptor D2L and serotonin receptor 5-HT2A are modulated.In a further particular variation, at least adrenergic receptors α1D,α2A, α2B and serotonin receptor 5-HT6 are modulated. In anotherparticular variation, at least adrenergic receptors α1D, α2A, α2B,serotonin receptor 5-HT6 and one or more of serotonin receptor 5-HT7,5-HT2A, 5-HT2C and histamine receptor H1 and H2 are modulated. In afurther particular variation, histamine receptor H1 is modulated. Inanother variation, compounds of the invention exhibit any receptormodulation activity detailed herein and further stimulate neuriteoutgrowth and/or neurogenesis and/or enhance neurotrophic effects.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-D show the effect of compounds 395, 68, 250, and 20 atdifferent concentrations on neurite outgrowth using cortical neurons.Asterisk (*) indicates significant difference over control group. FIG.1E shows the effect of compound 395 at different concentrations onneurite outgrowth using mixed cortical cultures.

FIGS. 2A and 2B display the recognition score and the percentage of goodlearners in scopolamine treated rats treated with compound 225 atdifferent concentrations. FIGS. 2C and 2D display the recognition scoreand the percentage of good learners in scopolamine treated rats treatedwith compound 68 at different concentrations. FIGS. 2E and 2F displaythe recognition score and the percentage of good learners in scopolaminetreated rats treated with compound 395 at different concentrations.

FIG. 3A displays a time course for the effects of clozapine and compound36 on total distance traveled in the OF during the 90-min test period.FIGS. 3B and 3C display the effect of clozapine and compound 36 on totaldistance traveled. Data were summed over the 30 min (B) prior to PCPinjection (baseline) and during the 60 min post PCP injection (C) andrepresent mean±SEM. Asterisk (*p<0.05) indicates significant differencecompared to DMSO-PCP. Pound sign (#p<0.05) indicates significantdifference compared to Vehicle-PCP. FIG. 3D displays a time course forthe effects of clozapine and compound 36 on total rearing during the90-min test period. Data represent mean±SEM. FIGS. 3E and 3F display theeffects of clozapine and compound 36 on total rearing. Data were summedover the 30 min (E) prior to PCP injection (baseline) and during the 60min post PCP injection (F) and represent mean±SEM. Asterisk (*p<0.05)indicates significant difference compared to DMSO-PCP. Pound sign(#p<0.05) indicates significant difference compared to Vehicle-PCP.

FIG. 4A displays a time course for the effects of clozapine and compound247 on total distance traveled during the 90-min test period. FIGS. 4Band 4C display the effects of clozapine and compound 247 on totaldistance traveled. Data were summed over the 30 minutes (B) prior to PCPinjection (baseline) and during the 60 min post-PCP injection (C) andrepresent mean±SEM. Asterisk (*) indicates significant difference fromPBS, p<0.05; Pound sign (#) indicates significant difference from DMSO,p<0.05.

FIG. 5A indicates glutamate-induced Ca uptake into synaptosomes forcompounds C 4-1, C 4-5, C 4-4).

FIG. 5B indicates glutamate-induced Ca uptake into synaptosomes forcompounds C 4-6, C 4-7.

FIG. 6A indicates glutamate-induced Ca uptake into synaptosomes forcompounds C 1-1, C 1-5.

FIG. 6B indicates glutamate-induced Ca uptake into synaptosomes forcompounds C 1-7.

FIG. 6C indicates glutamate-induced Ca uptake into synaptosomes forcompounds C 1-6.

FIG. 6D indicates glutamate-induced Ca uptake into synaptosomes forcompounds C 1-4, C 1-8.

FIG. 7 indicates glutamate-induced Ca uptake into synaptosomes forcompounds C 4-3, C 2-1.

FIG. 8 displays the action of C 4-1, C 4-5, and C 4-4 on the currents ofAMPA receptors in rat Purkinje cells.

FIG. 9 displays the action of C 4-6 and C 4-7 on the currents of AMPAreceptors in rat Purkinje cells.

FIG. 10 displays the action of C 1-1 and C 1-5 on the currents of AMPAreceptors in rat Purkinje cells.

FIG. 11 shows the comparative effect of dimebon and cyclothiazide onAMPA-receptors currents.

FIG. 12 displays the action of compounds C 1-4, C 1-6, C 1-8 and C 4-3on the kainic acid-induced currents in Purkinje cells.

FIG. 13 displays the influence of compounds on initial rate (Vi) ofCa²⁺-induced decrease of A₅₄₀ of mitochondrial suspension.

FIG. 14 displays the effects of various doses of dimebon on the durationof exploration of familiar and new objects.

FIG. 15 displays the effects of various doses of dimebon on the durationof exploration of objects in familiar and new locations.

FIG. 16 displays the effects of various doses of C 4-1 compound on theduration of exploration of objects in familiar and new locations.

FIG. 17 displays the effects of various doses of C 4-4 compound on theduration of exploration of objects in familiar and new locations.

FIG. 18 displays the effects of various doses of C 4-5 compound onduration of exploration of objects in familiar and new locations.

FIG. 19 displays the effects of various doses of C 4-6 compound onduration of exploration of objects in familiar and new locations.

FIG. 20 displays the effects of various doses of C 4-7 compound onduration of exploration of objects in familiar and new locations.

FIG. 21 displays the effects of various doses of C-1-1 compound onduration of exploration of objects in familiar and new locations.

FIG. 22 displays the effects of various doses of C 1-5 compound onduration of exploration of objects in familiar and new locations.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless clearly indicated otherwise, use of the terms “a”, “an” and thelike refers to one or more.

The term “about” as used herein refers to the usual range of variationfor the respective value readily known to the skilled person in thistechnical field. Reference to “about” a value or parameter hereinincludes (and describes) embodiments that are directed to that value orparameter per se.

As used herein, the term “aminergic G protein-coupled receptors” refersto a family of transmembrane proteins involved in cellularcommunication. Aminergic G protein coupled receptors are activated bybiogenic amines and represent a subclass of the superfamily of G proteincoupled receptors, which are structurally characterized by seventransmembrane helices. Aminergic G protein-coupled receptors include butare not limited to adrenergic receptors, serotonin receptors, dopaminereceptors, histamine receptors and imidazoline receptors.

As used herein, the term “adrenergic receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toan adrenergic receptor or reduces or eliminates or increases or enhancesor mimics an activity of an adrenergic receptor. As such, an “adrenergicreceptor modulator” encompasses both an adrenergic receptor antagonistand an adrenergic receptor agonist. In some aspects, the adrenergicreceptor modulator binds to or inhibits binding to a ligand to anα1-adrenergic receptor (e.g., α1A, α1B and/or α1D) and/or aα2-adrenergic receptor (e.g., α2A, α2B and/or α2C) and/or reduces oreliminates or increases or enhances or mimics an activity of aα1-adrenergic receptor (e.g., α1A, α1B and/or α1D) and/or aα2-adrenergic receptor (e.g., α2A, α2B and/or α2C) in a reversible orirreversible manner. In some aspects, the adrenergic receptor modulatorinhibits binding of a ligand by at least about or about any one of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in theassays described herein. In some aspects, the adrenergic receptormodulator reduces an activity of an adrenergic receptor by at least orabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the adrenergic receptor modulator or compared to thecorresponding activity in other subjects not receiving the adrenergicreceptor modulator. In some aspects, the adrenergic receptor modulatorenhances an activity of an adrenergic receptor by at least about orabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or200% or 300% or 400% or 500% or more as compared to the correspondingactivity in the same subject prior to treatment with the adrenergicreceptor modulator or compared to the corresponding activity in othersubjects not receiving the adrenergic receptor modulator. In someaspects, the adrenergic receptor modulator is capable of binding to theactive site of an adrenergic receptor (e.g., a binding site for aligand). In some embodiments, the adrenergic receptor modulator iscapable of binding to an allosteric site of an adrenergic receptor.

As used herein, the term “dopamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa dopamine receptor or reduces or eliminates or increases or enhances ormimics an activity of a dopamine receptor. As such, a “dopamine receptormodulator” encompasses both a dopamine receptor antagonist and adopamine receptor agonist. In some aspects, the dopamine receptormodulator binds to or inhibits binding of a ligand to a dopamine-1 (D1)and/or a dopamine-2 (D2) receptor or reduces or eliminates or increasesor enhances or mimics an activity of a dopamine-1 (D1) and/or adopamine-2 (D2) receptor in a reversible or irreversible manner.Dopamine D2 receptors are divided into two categories, D2L and D2S,which are formed from a single gene by differential splicing. D2Lreceptors have a longer intracellular domain than D2S. In someembodiments, the dopamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the dopamine receptor modulator reduces anactivity of a dopamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thedopamine receptor modulator or compared to the corresponding activity inother subjects not receiving the dopamine receptor modulator. In someembodiments, the dopamine receptor modulator enhances an activity of adopamine receptor by at least about or about any of 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% ormore as compared to the corresponding activity in the same subject priorto treatment with the dopamine receptor modulator or compared to thecorresponding activity in other subjects not receiving the dopaminereceptor modulator. In some embodiments, the dopamine receptor modulatoris capable of binding to the active site of a dopamine receptor (e.g., abinding site for a ligand). In some embodiments, the dopamine receptormodulator is capable of binding to an allosteric site of a dopaminereceptor.

As used herein, the term “serotonin receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa serotonin receptor or reduces or eliminates or increases or enhancesor mimics an activity of a serotonin receptor. As such, a “serotoninreceptor modulator” encompasses both a serotonin receptor antagonist anda serotonin receptor agonist. In some embodiments, the serotoninreceptor modulator binds to or inhibits binding of a ligand to a 5-HT1Aand/or a 5-HT1B and/or a 5-HT2A and/or a 5-HT2B and/or a 5-HT2C and/or a5-HT3 and/or a 5-HT4 and/or a 5-HT6 and/or a 5-HT7 receptor or reducesor eliminates or increases or enhances or mimics an activity of a 5-HT1Aand/or a 5-HT1B and/or a 5-HT2A and/or a 5-HT2B and/or a 5-HT2C and/or a5-HT3 and/or a 5-HT4 and/or a 5-HT6 and/or a 5-HT7 receptor in areversible or irreversible manner. In some embodiments, the serotoninreceptor modulator inhibits binding of a ligand by at least about orabout any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined in the assays described herein. In some embodiments,the serotonin receptor modulator reduces an activity of a serotoninreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100% as compared to the corresponding activity inthe same subject prior to treatment with the serotonin receptormodulator or compared to the corresponding activity in other subjectsnot receiving the serotonin receptor modulator. In some embodiments, theserotonin receptor modulator enhances an activity of a serotoninreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more ascompared to the corresponding activity in the same subject prior totreatment with the serotonin receptor modulator or compared to thecorresponding activity in other subjects not receiving the serotoninreceptor modulator. In some embodiments, the serotonin receptormodulator is capable of binding to the active site of a serotoninreceptor (e.g., a binding site for a ligand). In some embodiments, theserotonin receptor modulator is capable of binding to an allosteric siteof a serotonin receptor.

As used herein, the term “histamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa histamine receptor or reduces or eliminates or increases or enhancesor mimics an activity of a histamine receptor. As such, a “histaminereceptor modulator” encompasses both a histamine receptor antagonist anda histamine receptor agonist. In some embodiments, the histaminereceptor modulator binds to or inhibits binding of a ligand to ahistamine H1 and/or H2 and/or H3 receptor or reduces or eliminates orincreases or enhances or mimics an activity of a histamine H1 and/or H2and/or H3 receptor in a reversible or irreversible manner. In someembodiments, the histamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the histamine receptor modulator reduces anactivity of a histamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thehistamine receptor modulator or compared to the corresponding activityin other subjects not receiving the histamine receptor modulator. Insome embodiments, the histamine receptor modulator enhances an activityof a histamine receptor by at least about or about any of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500%or more as compared to the corresponding activity in the same subjectprior to treatment with the histamine receptor modulator or compared tothe corresponding activity in other subjects not receiving the histaminereceptor modulator. In some embodiments, the histamine receptormodulator is capable of binding to the active site of a histaminereceptor (e.g., a binding site for a ligand). In some embodiments, thehistamine receptor modulator is capable of binding to an allosteric siteof a histamine receptor.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to human, bovine, primate,equine, canine, feline, porcine, and ovine animals. Thus, the inventionfinds use in both human medicine and in the veterinary context,including use in agricultural animals and domestic pets. The individualmay be a human who has been diagnosed with or is suspected of having acognitive disorder, a psychotic disorder, a neurotransmitter-mediateddisorder and/or a neuronal disorder. The individual may be a human whoexhibits one or more symptoms associated with a cognitive disorder, apsychotic disorder, a neurotransmitter-mediated disorder and/or aneuronal disorder. The individual may be a human who has a mutated orabnormal gene associated with a cognitive disorder, a psychoticdisorder, a neurotransmitter-mediated disorder and/or a neuronaldisorder. The individual may be a human who is genetically or otherwisepredisposed to developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results, including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, alleviation of a symptom and/or diminishment of theextent of a symptom and/or preventing a worsening of a symptomassociated with a disease or condition. In one variation, beneficial ordesired clinical results include, but are not limited to, alleviation ofa symptom and/or diminishment of the extent of a symptom and/orpreventing a worsening of a symptom associated with a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. Preferably, treatment of a disease orcondition with a compound of the invention or a pharmaceuticallyacceptable salt thereof is accompanied by no or fewer side effects thanare associated with currently available therapies for the disease orcondition and/or improves the quality of life of the individual.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of Alzheimer's disease is a method that reducesprobability of disease development in a given time frame and/or reducesextent of the disease in a given time frame, when compared to not usingthe method. Such comparisons are typically based on clinical studies,using a statistically significant number of subjects. For example,Alzheimer's disease development can be detected using standard clinicaltechniques, such as routine neurological examination, patient interview,neuroimaging, detecting alterations of levels of specific proteins inthe serum or cerebrospinal fluid (e.g., amyloid peptides and Tau),computerized tomography (CT) or magnetic resonance imaging (MRI).Similar techniques are known in the art for other diseases andconditions. Development may also refer to disease progression that maybe initially undetectable and includes occurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder that canbe treated with a compound of the invention. An individual “at risk” mayor may not have a detectable disease or condition, and may or may nothave displayed detectable disease prior to the treatment methodsdescribed herein. “At risk” denotes that an individual has one or moreso-called risk factors, which are measurable parameters that correlatewith development of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. For example, individuals at risk for Alzheimer'sdisease include, e.g., those having relatives who have experienced thisdisease and those whose risk is determined by analysis of genetic orbiochemical markers. Genetic markers of risk for Alzheimer's diseaseinclude mutations in the APP gene, particularly mutations at position717 and positions 670 and 671 referred to as the Hardy and Swedishmutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Othermarkers of risk are mutations in the presenilin genes (e.g., PS1 orPS2), ApoE4 alleles, family history of Alzheimer's disease,hypercholesterolemia and/or atherosclerosis. Other such factors areknown in the art for other diseases and conditions.

As used herein, the term “pro-cognitive” includes but is not limited toan improvement of one or more mental processes such as memory,attention, perception and/or thinking, which may be assessed by methodsknown in the art.

As used herein, the term “neurotrophic” effects includes but is notlimited to effects that enhance neuron function such as growth, survivaland/or neurotransmitter synthesis.

As used herein, the term “cognitive disorders” refers to and intendsdiseases and conditions that are believed to involve or be associatedwith or do involve or are associated with progressive loss of structureand/or function of neurons, including death of neurons, and where acentral feature of the disorder may be the impairment of cognition(e.g., memory, attention, perception and/or thinking). These disordersinclude pathogen-induced cognitive dysfunction, e.g. HIV associatedcognitive dysfunction and Lyme disease associated cognitive dysfunction.Examples of cognitive disorders include Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis(ALS), autism, mild cognitive impairment (MCI), stroke, traumatic braininjury (TBI) and age-associated memory impairment (AAMI).

As used herein, the term “psychotic disorders” refers to and intendsmental diseases or conditions that are believed to cause or do causeabnormal thinking and perceptions. Psychotic disorders are characterizedby a loss of reality which may be accompanied by delusions,hallucinations (perceptions in a conscious and awake state in theabsence of external stimuli which have qualities of real perception, inthat they are vivid, substantial, and located in external objectivespace), personality changes and/or disorganized thinking. Other commonsymptoms include unusual or bizarre behavior, as well as difficulty withsocial interaction and impairment in carrying out the activities ofdaily living. Exemplary psychotic disorders are schizophrenia, bipolardisorders, psychosis, anxiety and depression.

As used herein, the term “neurotransmitter-mediated disorders” refers toand intends diseases or conditions that are believed to involve or beassociated with or do involve or are associated with abnormal levels ofneurotransmitters such as histamine, serotonin, dopamine, norepinephrineor impaired function of aminergic G protein-coupled receptors. Exemplaryneurotransmitter-mediated disorders include spinal cord injury, diabeticneuropathy, allergic diseases and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited, to Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barre syndrome, mild cognitiveimpairment, schizophrenia, anxiety, multiple sclerosis, stroke,traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases.

As used herein, the term “neuronal disorders” refers to and intendsdiseases or conditions that are believed to involve, or be associatedwith, or do involve or are associated with neuronal cell death and/orimpaired neuronal function or decreased neuronal function. Exemplaryneuronal indications include neurodegenerative diseases and disorderssuch as Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), Parkinson's disease, canine cognitive dysfunctionsyndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease,Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorderinvolving cerebral circulation, such as ischemic or hemorrhagic strokeor other cerebral hemorrhagic insult, age-associated memory impairment(AAMI), mild cognitive impairment (MCI), injury-related mild cognitiveimpairment (MCI), post-concussion syndrome, post-traumatic stressdisorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronaldeath mediated ocular disorder, macular degeneration, age-relatedmacular degeneration, autism, including autism spectrum disorder,Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cordinjury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis,diabetic neuropathy, fibromyalgia, neuropathy associated with spinalcord injury, schizophrenia, bipolar disorder, psychosis, anxiety ordepression.

As used herein, the term “neuron” represents a cell of ectodermalembryonic origin derived from any part of the nervous system of ananimal. Neurons express well-characterized neuron-specific markers,including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2,and class III tubulin. Included as neurons are, for example,hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory,sympathetic, septal cholinergic, and cerebellar neurons.

As used herein, the term “neurite outgrowth” or “neurite activation”refers to the extension of existing neuronal processes (e.g., axons anddendrites) and the growth or sprouting of new neuronal processes (e.g.,axons and dendrites). Neurite outgrowth or neurite activation may alterneural connectivity, resulting in the establishment of new synapses orthe remodeling of existing synapses.

As used herein, the term “neurogenesis” refers to the generation of newnerve cells from undifferentiated neuronal progenitor cells, also knownas multipotential neuronal stem cells. Neurogenesis actively producesnew neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/orother neural lineages. Much neurogenesis occurs early in humandevelopment, though it continues later in life, particularly in certainlocalized regions of the adult brain.

As used herein, the term “neural connectivity” refers to the number,type, and quality of connections (“synapses”) between neurons in anorganism. Synapses form between neurons, between neurons and muscles (a“neuromuscular junction”), and between neurons and other biologicalstructures, including internal organs, endocrine glands, and the like.Synapses are specialized structures by which neurons transmit chemicalor electrical signals to each other and to non-neuronal cells, muscles,tissues, and organs. Compounds that affect neural connectivity may do soby establishing new synapses (e.g., by neurite outgrowth or neuriteactivation) or by altering or remodeling existing synapses. Synapticremodeling refers to changes in the quality, intensity or type of signaltransmitted at particular synapses.

As used herein, the term “neuropathy” refers to a disorder characterizedby altered function and/or structure of motor, sensory, and autonomicneurons of the nervous system, initiated or caused by a primary lesionor other dysfunction of the nervous system. Patterns of peripheralneuropathy include polyneuropathy, mononeuropathy, mononeuritismultiplex and autonomic neuropathy. The most common form is(symmetrical) peripheral polyneuropathy, which mainly affects the feetand legs. A radiculopathy involves spinal nerve roots, but if peripheralnerves are also involved the term radiculoneuropathy is used. The formof neuropathy may be further broken down by cause, or the size ofpredominant fiber involvement, e.g. large fiber or small fiberperipheral neuropathy. Central neuropathic pain can occur in spinal cordinjury, multiple sclerosis, and some strokes, as well as fibromyalgia.Neuropathy may be associated with varying combinations of weakness,autonomic changes and sensory changes. Loss of muscle bulk orfasciculations, a particular fine twitching of muscle may also be seen.Sensory symptoms encompass loss of sensation and “positive” phenomenaincluding pain. Neuropathies are associated with a variety of disorders,including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiplesclerosis, and herpes zoster infection, as well as with spinal cordinjury and other types of nerve damage.

As used herein, the term “Alzheimer's disease” refers to a degenerativebrain disorder characterized clinically by progressive memory deficits,confusion, behavioral problems, inability to care for oneself, gradualphysical deterioration and, ultimately, death. Histologically, thedisease is characterized by neuritic plaques, found primarily in theassociation cortex, limbic system and basal ganglia. The majorconstituent of these plaques is amyloid beta peptide (Aβ), which is thecleavage product of beta amyloid precursor protein (βAPP or APP). APP isa type I transmembrane glycoprotein that contains a large ectopicN-terminal domain, a transmembrane domain and a small cytoplasmicC-terminal tail. Alternative splicing of the transcript of the singleAPP gene on chromosome 21 results in several isoforms that differ in thenumber of amino acids. Aβ appears to have a central role in theneuropathology of Alzheimer's disease. Familial forms of the diseasehave been linked to mutations in APP and the presenilin genes (Tanzi etal., 1996, Neurobiol. Dis., 3:159-168; Hardy, 1996, Ann. Med.,28:255-258). Diseased-linked mutations in these genes result inincreased production of the 42-amino acid form of Aβ, the predominantform found in amyloid plaques. Mitochondrial dysfunction has also beenreported to be an important component of Alzheimer's disease (Bubber etal., Mitochondrial abnormalities in Alzheimer brain: MechanisticImplications, Ann Neurol., 2005, 57(5), 695-703; Wang et al., Insightsinto amyloid-β-induced mitochondrial dysfunction in Alzheimer disease,Free Radical Biology & Medicine, 2007, 43, 1569-1573; Swerdlow et al.,Mitochondria in Alzheimer's disease, Int. Rev. Neurobiol., 2002, 53,341-385; and Reddy et al., Are mitochondria critical in the pathogenesisof Alzheimer's disease?, Brain Res Rev. 2005, 49(3), 618-32). It hasbeen proposed that mitochondrial dysfunction has a causal relationshipwith neuronal function (including neurotransmitter synthesis andsecretion) and viability. Compounds which stabilize mitochondria maytherefore have a beneficial impact on Alzheimer's patients.

As used herein, the term “Huntington's disease” refers to a fatalneurological disorder characterized clinically by symptoms such asinvoluntary movements, cognition impairment or loss of cognitivefunction and a wide spectrum of behavioral disorders. Common motorsymptoms associated with Huntington's disease include chorea(involuntary writhing and spasming), clumsiness, and progressive loss ofthe abilities to walk, speak (e.g., exhibiting slurred speech) andswallow. Other symptoms of Huntington's disease can include cognitivesymptoms such as loss of intellectual speed, attention and short-termmemory and/or behavioral symptoms that can span the range of changes inpersonality, depression, irritability, emotional outbursts and apathy.Clinical symptoms typically appear in the fourth or fifth decade oflife. Huntington's disease is a devastating and often protractedillness, with death usually occurring approximately 10-20 years afterthe onset of symptoms. Huntington's disease is inherited through amutated or abnormal gene encoding an abnormal protein called the mutanthuntingtin protein; the mutated huntintin protein produces neuronaldegeneration in many different regions of the brain. The degenerationfocuses on neurons located in the basal ganglia, structures deep withinthe brain that control many important functions including coordinatingmovement, and on neurons on the outer surface of the brain or cortex,which controls thought, perception and memory.

“Amyotrophic lateral sclerosis” or “ALS” are used herein to denote aprogressive neurodegenerative disease that affects upper motor neurons(motor neurons in the brain) and/or lower motor neurons (motor neuronsin the spinal cord) and results in motor neuron death. As used herein,the term “ALS” includes all of the classifications of ALS known in theart, including, but not limited to classical ALS (typically affectingboth lower and upper motor neurons), Primary Lateral Sclerosis (PLS,typically affecting only the upper motor neurons), Progressive BulbarPalsy (PBP or Bulbar Onset, a version of ALS that typically begins withdifficulties swallowing, chewing and speaking), Progressive MuscularAtrophy (PMA, typically affecting only the lower motor neurons) andfamilial ALS (a genetic version of ALS).

The term “Parkinson's disease” as used herein refers to any medicalcondition wherein an individual experiences one or more symptomsassociated with Parkinson's disease, such as without limitation one ormore of the following symptoms: rest tremor, cogwheel rigidity,bradykinesia, postural reflex impairment, symptoms having good responseto 1-dopa treatment, the absence of prominent oculomotor palsy,cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia.In a specific embodiment, the present invention is utilized for thetreatment of a dopaminergic dysfunction-related disorder. In a specificembodiment, the individual with Parkinson's disease has a mutation orpolymorphism in a synuclein, parkin or NURR1 nucleic acid that isassociated with Parkinson's disease. In one embodiment, the individualwith Parkinson's disease has defective or decreased expression of anucleic acid or a mutation in a nucleic acid that regulates thedevelopment and/or survival of dopaminergic neurons.

As used herein, the term “canine cognitive dysfunction syndrome,” or“CCDS” refers to an age-related deterioration of mental functiontypified by multiple cognitive impairments that affect an afflictedcanine's ability to function normally. The decline in cognitive abilitythat is associated with CCDS cannot be completely attributed to ageneral medical condition such as neoplasia, infection, sensoryimpairment, or organ failure. Diagnosis of CCDS in canines, such asdogs, is generally a diagnosis of exclusion, based on thorough behaviorand medical histories and the presence of clinical symptoms of CCDS thatare unrelated to other disease processes. Owner observation ofage-related changes in behavior is a practical means used to detect thepossible onset of CCDS in aging domestic dogs. A number of laboratorycognitive tasks may be used to help diagnose CCDS, while blood counts,chemistry panels and urinalysis can be used to rule out other underlyingdiseases that could mimic the clinical symptoms of CCDS. Symptoms ofCCDS include memory loss, which in domestic dogs may be manifested bydisorientation and/or confusion, decreased or altered interaction withfamily members and/or greeting behavior, changes in sleep-wake cycle,decreased activity level, and loss of house training or frequent,inappropriate elimination. A canine suffering from CCDS may exhibit oneor more of the following clinical or behavioral symptoms: decreasedappetite, decreased awareness of surroundings, decreased ability torecognize familiar places, people or other animals, decreased hearing,decreased ability to climb up and down stairs, decreased tolerance tobeing alone, development of compulsive behavior or repetitive behaviorsor habits, circling, tremors or shaking, disorientation, decreasedactivity level, abnormal sleep wake cycles, loss of house training,decreased or altered responsiveness to family members, and decreased oraltered greeting behavior. CCDS can dramatically affect the health andwell-being of an afflicted canine. Moreover, the companionship offeredby a pet with CCDS can become less rewarding as the severity of thedisease increases and its symptoms become more severe.

As used herein, the term “age-associated memory impairment” or “AAMI”refers to a condition that may be identified as GDS stage 2 on theglobal deterioration scale (GDS) (Reisberg, et al. (1982) Am. J.Psychiatry 139: 1136-1139) which differentiates the aging process andprogressive degenerative dementia in seven major stages. The first stageof the GDS is one in which individuals at any age have neithersubjective complaints of cognitive impairment nor objective evidence ofimpairment. These GDS stage 1 individuals are considered normal. Thesecond stage of the GDS applies to those generally elderly persons whocomplain of memory and cognitive functioning difficulties such as notrecalling names as well as they could five or ten years previously ornot recalling where they have placed things as well as they could fiveor ten years previously. These subjective complaints appear to be verycommon in otherwise normal elderly individuals. AAMI refers to personsin GDS stage 2, who may differ neurophysiologically from elderly personswho are normal and free of subjective complaints, i.e., GDS stage 1. Forexample, AAMI subjects have been found to have more electrophysiologicslowing on a computer analyzed EEG than GDS stage 1 elderly persons(Prichep, John, Ferris, Reisberg, et al. (1994) Neurobiol. Aging 15:85-90).

As used herein, the term “mild cognitive impairment” or “MCI” refers toa type of cognitive disorder characterized by a more pronounceddeterioration in cognitive functions than is typical for normalage-related decline. As a result, elderly or aged patients with MCI havegreater than normal difficulty performing complex daily tasks andlearning, but without the inability to perform normal social, everyday,and/or professional functions typical of patients with Alzheimer'sdisease, or other similar neurodegenerative disorders eventuallyresulting in dementia. MCI is characterized by subtle, clinicallymanifest deficits in cognition, memory, and functioning, amongst otherimpairments, which are not of sufficient magnitude to fulfill criteriafor diagnosis of Alzheimer's disease or other dementia. MCI alsoencompasses injury-related MCI, defined herein as cognitive impairmentresulting from certain types of injury, such as nerve injury (i.e.,battlefield injuries, including post-concussion syndrome, and the like),neurotoxic treatment (i.e., adjuvant chemotherapy resulting in “chemobrain” and the like), and tissue damage resulting from physical injuryor other neurodegeneration, which is separate and distinct from mildcognitive impairment resulting from stroke, ischemia, hemorrhagicinsult, blunt force trauma, and the like.

As used herein, the term “traumatic brain injury” or “TBI” refers to abrain injury caused by a sudden trauma, such as a blow or jolt or apenetrating head injury, which disrupts the function or damages thebrain. Symptoms of TBI can range from mild, moderate to severe and cansignificantly affect many cognitive (deficits of language andcommunication, information processing, memory, and perceptual skills),physical (ambulation, balance, coordination, fine motor skills,strength, and endurance), and psychological skills.

“Neuronal death mediated ocular disease” intends an ocular disease inwhich death of the neuron is implicated in whole or in part. The diseasemay involve death of photoreceptors. The disease may involve retinalcell death. The disease may involve ocular nerve death by apoptosis.Particular neuronal death mediated ocular diseases include but are notlimited to macular degeneration, glaucoma, retinitis pigmentosa,congenital stationary night blindness (Oguchi disease), childhood onsetsevere retinal dystrophy, Leber congenital amaurosis, Bardet-Biedlesyndrome, Usher syndrome, blindness from an optic neuropathy, Leber'shereditary optic neuropathy, color blindness and Hansen-Larson-Bergsyndrome.

As used herein, the term “macular degeneration” includes all forms andclassifications of macular degeneration known in the art, including, butnot limited to diseases that are characterized by a progressive loss ofcentral vision associated with abnormalities of Bruch's membrane, thechoroid, the neural retina and/or the retinal pigment epithelium. Theterm thus encompasses disorders such as age-related macular degeneration(ARMD) as well as rarer, earlier-onset dystrophies that in some casescan be detected in the first decade of life. Other maculopathies includeNorth Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt'sdisease, pattern dystrophy, Best disease, and Malattia Leventinese.

As used herein, the term “autism” refers to a brain development disorderthat impairs social interaction and communication and causes restrictedand repetitive behavior, typically appearing during infancy or earlychildhood. The cognitive and behavioral defects are thought to result inpart from altered neural connectivity. Autism encompasses relateddisorders sometimes referred to as “autism spectrum disorder,” as wellas Asperger syndrome and Rett syndrome.

As used herein, the term “nerve injury” or “nerve damage” refers tophysical damage to nerves, such as avulsion injury (i.e., where a nerveor nerves have been torn or ripped) or spinal cord injury (i.e., damageto white matter or myelinated fiber tracts that carry sensation andmotor signals to and from the brain). Spinal cord injury can occur frommany causes, including physical trauma (i.e., car accidents, sportsinjuries, and the like), tumors impinging on the spinal column,developmental disorders, such as spina bifida, and the like.

As used herein, the term “myasthenia gravis” or “MG” refers to anon-cognitive neuromuscular disorder caused by immune-mediated loss ofacetylcholine receptors at neuromuscular junctions of skeletal muscle.Clinically, MG typically appears first as occasional muscle weakness inapproximately two-thirds of patients, most commonly in the extraocularmuscles. These initial symptoms eventually worsen, producing droopingeyelids (ptosis) and/or double vision (diplopia), often causing thepatient to seek medical attention. Eventually, many patients developgeneral muscular weakness that may fluctuate weekly, daily, or even morefrequently. Generalized MG often affects muscles that control facialexpression, chewing, talking, swallowing, and breathing; before recentadvances in treatment, respiratory failure was the most common cause ofdeath.

As used herein, the term “Guillain-Barré syndrome” refers to anon-cognitive disorder in which the body's immune system attacks part ofthe peripheral nervous system. The first symptoms of this disorderinclude varying degrees of weakness or tingling sensations in the legs.In many instances the weakness and abnormal sensations spread to thearms and upper body. These symptoms can increase in intensity untilcertain muscles cannot be used at all and, when severe, the patient isalmost totally paralyzed. In these cases the disorder is lifethreatening—potentially interfering with breathing and, at times, withblood pressure or heart rate—and is considered a medical emergency. Mostpatients, however, recover from even the most severe cases ofGuillain-Barré syndrome, although some continue to have a certain degreeof weakness.

As used herein, the term “multiple sclerosis” or “MS” refers to anautoimmune condition in which the immune system attacks the centralnervous system (CNS), leading to demyelination of neurons. It may causenumerous symptoms, many of which are non-cognitive, and often progressesto physical disability. MS affects the areas of the brain and spinalcord known as the white matter. White matter cells carry signals betweenthe grey matter areas, where the processing is done, and the rest of thebody. More specifically, MS destroys oligodendrocytes which are thecells responsible for creating and maintaining a fatty layer, known asthe myelin sheath, which helps the neurons carry electrical signals. MSresults in a thinning or complete loss of myelin and, less frequently,the cutting (transection) of the neuron's extensions or axons. When themyelin is lost, the neurons can no longer effectively conduct theirelectrical signals. Almost any neurological symptom can accompany thedisease. MS takes several forms, with new symptoms occurring either indiscrete attacks (relapsing forms) or slowly accumulating over time(progressive forms). Most people are first diagnosed withrelapsing-remitting MS but develop secondary-progressive MS (SPMS) aftera number of years. Between attacks, symptoms may go away completely, butpermanent neurological problems often persist, especially as the diseaseadvances.

As used herein, the term “schizophrenia” refers to a chronic, mentaldisorder characterized by one or more positive symptoms (e.g., delusionsand hallucinations) and/or negative symptoms (e.g., blunted emotions andlack of interest) and/or disorganized symptoms (e.g., disorganizedthinking and speech or disorganized perception and behavior).Schizophrenia as used herein includes all forms and classifications ofschizophrenia known in the art, including, but not limited to catatonictype, hebephrenic type, disorganized type, paranoid type, residual typeor undifferentiated type schizophrenia and deficit syndrome and/or thosedescribed in American Psychiatric Association: Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Washington D.C.,2000 or in International Statistical Classification of Diseases andRelated Health Problems, or otherwise known to those of skill in theart.

As used herein “geroprotective activity” or “geroprotector” means abiological activity that slows down ageing and/or prolongs life and/orincreases or improves the quality of life via a decrease in the amountand/or the level of intensity of pathologies or conditions that are notlife-threatening but are associated with the aging process and which aretypical for elderly people. Pathologies or conditions that are notlife-threatening but are associated with the aging process include suchpathologies or conditions as loss of sight (cataract), deterioration ofthe dermatohairy integument (alopecia), and an age-associated decreasein weight due to the death of muscular and/or fatty cells.

As used herein “allergic disease” refers to a disorder of the immunesystem which is characterized by excessive activation of mast cells andbasophils and production of IgE immunoglobulins, resulting in an extremeinflammatory response. It represents a form of hypersensitivity to anenvironmental substance known as allergen and is an acquired disease.Common allergic reactions include eczema, hives, hay fever, asthma, foodallergies, and reactions to the venom of stinging insects such as waspsand bees. Allergic reactions are accompanied by an excessive release ofhistamines, and can thus be treated with antihistaminic agents.

As used herein, by “combination therapy” is meant a therapy thatincludes two or more different compounds. Thus, in one aspect, acombination therapy comprising a compound detailed herein and anthercompound is provided. In some variations, the combination therapyoptionally includes one or more pharmaceutically acceptable carriers orexcipients, non-pharmaceutically active compounds, and/or inertsubstances. In various embodiments, treatment with a combination therapymay result in an additive or even synergistic (e.g., greater thanadditive) result compared to administration of a single compound of theinvention alone. In some embodiments, a lower amount of each compound isused as part of a combination therapy compared to the amount generallyused for individual therapy. Preferably, the same or greater therapeuticbenefit is achieved using a combination therapy than by using any of theindividual compounds alone. In some embodiments, the same or greatertherapeutic benefit is achieved using a smaller amount (e.g., a lowerdose or a less frequent dosing schedule) of a compound in a combinationtherapy than the amount generally used for individual compound ortherapy. Preferably, the use of a small amount of compound results in areduction in the number, severity, frequency, and/or duration of one ormore side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of acompound of the invention which in combination with its parameters ofefficacy and toxicity, as well as based on the knowledge of thepracticing specialist should be effective in a given therapeutic form.As is understood in the art, an effective amount may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and asingle agent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any of theco-administered compounds may optionally be lowered due to the combinedaction (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, i.e., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. A pharmaceutically acceptable salt intends ionicinteractions and not a covalent bond. As such, an N-oxide is notconsidered a salt. Such salts, for example, include: (1) acid additionsalts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, oxalic acid,propionic acid, succinic acid, maleic acid, tartaric acid and the like;(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase. Acceptable organic bases include ethanolamine, diethanolamine,triethanolamine and the like. Acceptable inorganic bases includealuminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like. Further examples ofpharmaceutically acceptable salts include those listed in Berge et al.,Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19.Pharmaceutically acceptable salts can be prepared in situ in themanufacturing process, or by separately reacting a purified compound ofthe invention in its free acid or base form with a suitable organic orinorganic base or acid, respectively, and isolating the salt thus formedduring subsequent purification. It should be understood that a referenceto a pharmaceutically acceptable salt includes the solvent additionforms or crystal forms thereof, particularly solvates or polymorphs.Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and are often formed during the process of crystallization.Hydrates are formed when the solvent is water, or alcoholates are formedwhen the solvent is alcohol. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, and solubility. Various factors suchas the recrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. In fused ringsystems, one or more of the rings can be aryl or heteroaryl. Acycloalkyl having more than one ring where at least one ring is aromaticmay be connected to the parent structure at either a non-aromatic ringposition or at an aromatic ring position. In one variation, a cycloalkylhaving more than one ring where at least one ring is aromatic isconnected to the parent structure at a non-aromatic ring position. Apreferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to13 annular carbon atoms. A more preferred cycloalkyl is a saturatedcyclic hydrocarbon having from 3 to 7 annular carbon atoms (a “C₃-C₇cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl and thelike.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include ethylene (—CH₂CH₂—) and propylene(—CH₂CH₂CH₂—).

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the later example can be attached to the cyclohexenyl moiety atany available position on the ring.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylinic unsaturation (i.e., having at least one moiety of theformula C≡C) and preferably having from 2 to 10 carbon atoms and morepreferably 3 to 8 carbon atoms.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents s including, but not limited to, substituents such asalkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—,heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, andsubstituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. Aheterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclicgroup having from 2 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy andthe like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like (e.g., oxide such as when an annularnitrogen is substituted with an oxide).

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. A“substituted aralkyl” refers to a residue in which an aryl moiety isattached to a substituted alkyl residue and wherein the aralkyl groupmay be attached to the parent structure at either the aryl or the alkylresidue.

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic,provided that both R_(a) and R_(b) groups are not H; or (b) R_(a) andR_(b) are joined together with the nitrogen atom to form a heterocyclicor substituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic or R_(a) and R_(b) groups canbe joined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminoacyl” refers to the group —NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂—alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-aryl, —NRSO₂-substituted aryl,—NRSO₂-heteroaryl, —NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic,and —NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂—substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic.

“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or from 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc., refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Carboxyl” refs to the group —C(O)OH.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

A composition of “substantially pure” compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure S compound means that the composition contains nomore than 15% or no more than 10% or no more than 5% or no more than 3%or no more than 1% of the R form of the compound.

Compounds of the Invention:

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and the appended claims. Thus,compounds of the invention include any compounds detailed herein. Theinvention includes the use of all of the compounds described herein,including any and all stereoisomers, salts and solvates of the compoundsdescribed as histamine receptor modulators. Further methods of using thecompounds of the invention are detailed throughout.

The invention embraces compounds of the Formula (I):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano or nitro or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

X¹ is N or CH;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl or is taken together with the carbon to whichit is attached and a geminal R^(8(a-f)) to form a cycloalkyl moiety or acarbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or a unsubstitutedheterocyclyl;

provided that: (i) when X¹ is N the compound is other than a compound inTable 1 or salt thereof; and (ii) the compound is other than thosecompounds listed in U.S. Pat. Nos. 6,187,785, 7,071,206, 3,409,628 and6,849,640 or in PCT Publication Nos. WO 2005/05591, WO 2007/041697 andWO 2007/087425. In another variation, the compounds of the invention,and methods of using the compounds detailed herein, encompass any of thecompounds of Formula (I), including those listed in Table 1 or a saltthereof. In one variation, the compound is of the formula (I) wherein R⁴is other than a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an aryloxy or an aralkyl. In one variation thecompound is of the formula (I) wherein R⁴ is other than a substituted orunsubstituted aryl. In another variation, the compound is of formula (I)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is N, provided that thecompound is other than a compound of 233x, 234x or 235x, or a salt orsolvate thereof. In another variation, the compound is of the formula(I) wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is N and R¹ is methyl.

In one variation, when the compound is of the formula (I) and X¹ is CH,then the compound is of the formula (AA) where X⁷-X¹⁰, R^(2a), R^(2b),R^(3a), R^(3a), R^(8a)-R^(8f), R^(10a), R^(10b), m, q and Q are asdefined in formula (I).

In one variation, the compound is of the formula (I) wherein thecompound further is a type 1 compound. In another variation, thecompound is of the formula (I) wherein the compound further is a type 2compound. In yet another variation, the compound is of the formula (I)wherein the compound further is a type 3 compound. In a furthervariation, the compound is of the formula (I) wherein the compoundfurther is a type 4 compound.

In one variation, a compound is of the formula (AA):

where:

X⁷-X¹⁰, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a)-R^(8f), R^(10a), R^(10b),m, q and Q are as defined in one variation in formula (I) and in anothervariation in formula (E) and either:

(a) each R^(a) and R^(b) is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic,provided that both R^(a) and R^(b) groups are not H, and one or more of(i)-(iii) apply:

-   -   (i) when m and q are 0, at least one of R^(a) and R^(b) is other        than methyl;    -   (ii) when m and q are 0, at least one of X⁷-X¹⁰ is other than        CH;    -   (iii) when m and q are 0, either (a) Q is a other than a        substituted or unsubstituted phenyl or (b) Q is a substituted or        unsubstituted heteroaryl, substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl or        substituted or a unsubstituted heterocyclyl; or

(b) R^(a) and R^(b) are joined together with the nitrogen atom to whichthey are attached to form a heterocyclic or substituted heterocyclicring,

or a pharmaceutically acceptable salt thereof.

In one variation of formula (AA), at least one of m and q is 1 andeither (a) each R^(a) and R^(b) group is independently selected from thegroup consisting of H, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic, provided that both R^(a) and R^(b) groups are not H; or(b) R^(a) and R^(b) are joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring.

In another variation, a compound is of the formula (AB):

where:

X⁷-X¹⁰, R¹, R^(3a), R^(3a), R^(8b)-R^(8f), R^(10a), R^(10b), m, q and Qare as defined in one variation in formula (I) and in another variationin formula (E) and either:

(a) each R^(a) and R^(b) is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic,provided that when m and q are 0, one or more of (i)-(v) apply:

-   -   (i) at least one of R^(8e) and R^(8f) is hydroxyl, C₁-C₈ alkyl        or R^(8e) and R^(8f) are taken together with the carbon to which        they are attached o form a cycloalkyl moiety or a carbonyl        moiety;    -   (ii) Q is a substituted aryl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl,        substituted or unsubstituted C₃₋₈ cycloalkenyl or a substituted        or unsubstituted heterocyclyl;    -   (iii) R^(a) and R^(b) are other than a substituted alkyl;    -   (iv) at least one of X⁷-X¹⁰ is other than CH; and    -   (v) R¹ is hydroxyl, nitro, cyano, halo, substituted or        unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈        alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,        perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy,        carboxyl, thiol, thioalkyl, acylamino, sulfonylamino, sulfonyl        or carbonylalkylenealkoxy; or

(b) R^(a) and R^(b) are joined together with the nitrogen atom to whichthey are attached to form a heterocyclic or substituted heterocyclicring,

or a pharmaceutically acceptable salt thereof.

In one variation of formula (AB), Q is other than a substituted phenyl.In another variation of formula (AB), each R^(a) and R^(b) isindependently selected from H, alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic.

In a further variation, a compound is of the formula (AC):

where:

X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a)-R^(8f), m, q and Qare as defined in one variation in formula (I) and in another variationin formula (E) and either:

(a) each R^(a) and R^(b) is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic,provided that when m and q are 0, one or more of (i)-(v) apply:

-   -   (i) R^(8e) and R^(8f) are independently H, hydroxyl, C₁-C₈ alkyl        or R^(8e) and R^(8f) are taken together with the carbon to which        they are attached to form a cycloalkyl moiety;    -   (ii) Q is a unsubstituted aryl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl,        substituted or unsubstituted C₃₋₈ cycloalkenyl or substituted or        a unsubstituted heterocyclyl;    -   (iii) R^(a) and R^(b) are other than a substituted alkyl;    -   (iv) at least one of X⁷-X¹⁰ is other than CH; and    -   (v) R¹ is hydroxyl, nitro, cyano, halo, substituted or        unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈        alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,        perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy,        carboxyl, thiol, thioalkyl, acylamino, sulfonylamino, sulfonyl        or carbonylalkylenealkoxy; or

(b) R^(a) and R^(b) are joined together with the nitrogen atom to whichthey are attached to form a heterocyclic or substituted heterocyclicring;

or a pharmaceutically acceptable salt thereof.

In a particular variation of formula (AC), Q is other than anunsubstituted phenyl. In another variation of formula (AC), each R^(a)and R^(b) is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl and substituted heterocyclyl.

In one variation, the invention embraces compounds of the formula (H):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, R^(2a) and R^(2b) are taken together to form acarbonyl moiety or R^(2a) and R^(2b) are taken together with the carbonto which they are attached to form a cycloalkyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(3a) and R^(3b)are taken together to form a carbonyl moiety or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,or is taken together with the carbon to which it is attached and ageminal R₈ to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxy, cyano, nitro, substitutedor unsubstituted amino, R^(10a) and R^(10b) are taken together to form acarbonyl or R^(10a) and R^(10b) are taken together with the carbon towhich they are attached to form a cycloalkyl moiety;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or a unsubstitutedheterocyclyl;

provided that exactly one of R¹, R^(2a), R^(2b), R^(10a) and R^(10b), issubstituted or unsubstituted amino;

or a salt thereof.

In another variation, the invention embraces compounds of the formula(A):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano or nitro or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl or is taken together with the carbon to whichit is attached and a geminal R^(8(a-f)) to form a cycloalkyl moiety or acarbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or a unsubstitutedheterocyclyl;

provided that the compound is other than (i) a compound in Table 1 orsalt thereof and (ii) the compound is other than any of compounds 229H,230, 241, 255, 256, 262 and 274 or a salt thereof. In another variation,the compounds of the invention, and methods of using the compounds andadministering the compounds as detailed herein, encompass any of thecompounds of formula A, including those listed in Table 1 or a saltthereof and compounds 229H, 230, 241, 255, 256, 262 and 274, or a saltthereof. In a further variation, the compound is of the formula (A)provided that the compound is other than (i) a compound in Table 1 orsalt thereof and (ii) the compound is other than any of compounds 229H,230, 241, 255, 256, 262 and 274 or a salt thereof and (iii) a compoundin Table 1A or salt thereof.

In one variation, the compound is of the formula (A) provided that: (i)it is other than a compound in Table 1 or salt thereof; and (ii) thecompound is other than those compounds listed in U.S. Pat. Nos.6,187,785, 7,071,206, 3,409,628 and 6,849,640 or in PCT Publication Nos.WO 2005/05591, WO 2007/041697 and WO 2007/087425. In another variation,the compounds of the invention, and methods of using the compoundsdetailed herein, encompass any of the compounds of formula A, includingthose listed in Table 1 or Table 1A or a salt thereof. In one variation,the compound is of the formula (A) wherein R⁴ is other than asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, an aryloxy or an aralkyl. In one variation the compound isof the formula (A) wherein R⁴ is other than a substituted orunsubstituted aryl. In another variation, the compound is of formula (A)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is N, provided that thecompound is other than a compound of 233x, 234x or 235x, or a salt orsolvate thereof. In another variation, the compound is of formula (A)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is N and R¹ is methyl.

In another variation, the invention embraces compounds of the formula(E):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety or R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(3a) and R^(3b)are taken together to form a carbonyl moiety or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,or is taken together with the carbon to which it is attached and ageminal R₈ to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a) and R^(10b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro orR^(10a) and R^(10b) are taken together to form a carbonyl moiety orR^(10a) and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl or substituted or a unsubstitutedheterocyclyl;

provided that (i) the compound is other than a compound in Table 1 orsalt thereof; (ii) the compound is other than a compound of Table 1A ora salt thereof and (iii) the compound is other than any of compounds229H, 230, 241, 255, 256, 262 and 274 or a salt thereof. In anothervariation, the compounds of the invention, and methods of using thecompounds and administering the compounds as detailed herein, encompassany of the compounds of formula (E), including those listed in Table 1and Table 1A or a salt thereof and compounds 229H, 230, 241, 255, 256,262 and 274, or a salt thereof. In one variation, Q is a substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl or substituted or a unsubstituted heterocyclyl. In anothervariation, the compound is of the formula (E) further provided that whenQ is a substituted or unsubstituted heteroaryl, it is other than athiazole, triazole, or oxadiazole. However, in another variation, thecompound is of the formula (E) and includes compounds in which Q is athiazole, triazole, or oxadiazole. In still another variation, thecompound is of the formula (E) further provided that the compound isother than a compound of formula (G). However, in another variation, thecompound is of the formula (E) and includes compounds that conform tothe formula (G).

In one variation, the compound is of the formula (E) wherein thecompound further is a type 1 compound. In another variation, thecompound is of the formula (E) wherein the compound further is a type 2compound. In yet another variation, the compound is of the formula (E)wherein the compound further is a type 3 compound. In a furthervariation, the compound is of the formula (E) wherein the compoundfurther is a type 4 compound.

In another variation, the invention embraces compounds of the formula(A) or (E) where at least one of m and q is 1 and where Q is asubstituted phenyl. In one variation, Q is a phenyl substituted with 0to 6 R⁹ moieties where each R⁹ is independently a halo, cyano, nitro,perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted orunsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino,acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl oraminocarbonylamino moiety. In another variation, Q is a phenylsubstituted with at least one alkyl, perhaloalkyl, halo, hydroxyl oralkoxy moiety. In still another variation, Q is a phenyl substitutedwith at least one alkyl, perhaloalkyl, halo, cyano, nitro, hydroxyl,alkoxy, or perhaloalkoxy moiety. In another such variation, Q is aphenyl substituted with two or three moieties selected from methyl,perhaloalkyl, halo, hydroxyl and alkoxy. In a particular variation, atleast one of m and q is 1, and Q is a phenyl substituted with at leastone of: methyl, trifluoromethyl, fluoro, chloro, hydroxyl, methoxy,ethoxy and isopropoxy. When Q is a phenyl substituted with two or threemoieties, the moieties may be the same or different. For example, whenat least one of m and q is 1, Q in one variation is difluorophenyl,dichlorophenyl, dimethoxyphenyl, di(trifluoromethyl)phenyl,trifluorophenyl, (fluoro)(chloro)phenyl,(fluoro)(trifluoromethyl)phenyl, (chloro)(trifluoromethyl)phenyl or(fluoro)(methoxy)phenyl. In one variation, when the compound is of theformula (A) or (E) and Q is a substituted phenyl, the substituent orsubstituents may be positioned at any available phenyl ring position.For example, singly-substituted phenyl groups may be substituted at theortho, meta or para-position of the phenyl group. Any available phenylring substitution pattern is suitable for di- or tri-substituted phenylgroups (e.g., at the ortho and para positions, at two ortho positions,at two meta positions, at the meta and para positions, at the ortho,meta and para positions, at two ortho and the para position, at twoortho and a meta position, or at two meta and a para or ortho position).In one variation, the compound is of the formula (A) or (E) where one ofm and q is 1 and the other is 0 and Q is a substituted phenyl. Infurther variation, the compound is of the formula (A) or (E) where bothm and q are 1 and Q is a substituted phenyl.

In another variation, the invention embraces compounds of the formula(A) or (E) where m and q are 0, Q is a substituted phenyl wherein thesubstituent is positioned at the ortho and/or meta position of thephenyl ring and the para-position bears a hydrogen and R¹ is methyl orethyl. In another variation, the invention embraces compounds of theformula (A) or (E) where m and q are 0, Q is a substituted phenylwherein the substituent is positioned at the ortho and/or meta positionof the phenyl ring and the para-position bears a hydrogen and R¹ ismethyl or ethyl, provided that Q is other than 3-methylphenyl. In onevariation, Q is a mono-substituted phenyl that is substituted at theortho or meta position. In one variation, Q is a mono-substituted phenylthat is substituted at the ortho position. Suitable phenyl substituentsand substitution patterns include those detailed in the proceedingparagraph.

In another variation, the invention embraces compounds of the formula(A) or (E) where m and q are 0, Q is a substituted phenyl and R¹ ismethyl, provided that at least one of (i)-(iii) applies: (i) when R^(8e)and R^(8f) are taken together with the carbon to which they are attachedto form a carbonyl, X⁹ is other than CR⁴ where R⁴ is methyl; (ii) Q is asubstituted phenyl having at least one fluoro substituent; and (iii)when Q is 4-methoxyphenyl, X⁹ is other than CR⁴ where R⁴ is chloro. Inanother variation, the invention embraces compounds of the formula (A)or (E) where m and q are 0, Q is a substituted phenyl and R¹ is methyl,provided that at least one of (i)-(iii) applies: (i) when R^(8e) andR^(8f) are taken together with the carbon to which they are attached toform a carbonyl, X⁹ is other than CR⁴ where R⁴ is OCH₃; (ii) Q is asubstituted phenyl having at least one fluoro substituent provided thatQ is other than 4-fluorophenyl; and (iii) when Q is 4-methoxyphenyl, X⁹is other than CR⁴ where R⁴ is chloro.

In one variation, the compound is of the formula (A) or (E) where one ofm and q is 1 and the other is 0 and R^(8e) and R^(8f) are taken togetherwith the carbon to which they are attached to form a carbonyl. In onevariation, the compound is of the formula (A) or (E) where one of m andq is 1 and the other is 0 and R^(8e) and R^(8f) are taken together withthe carbon to which they are attached to form a carbonyl provided that(i) R¹ is other than isopropyl and/or (ii) Q is other than a substitutedpiperizinyl. In another variation, the compound is of the formula (A) or(E) where one of m and q is 1 and the other is 0, R^(8e) and R^(8f) aretaken together with the carbon to which they are attached to form acarbonyl and R¹ is CH₃ or H. In still a further variation, the compoundis of the formula (A) or (E) where one of m and q is 1 and the other is0, R^(8e) and R^(8f) are taken together with the carbon to which theyare attached to form a carbonyl, R¹ is CH₃ or H, X⁷, X⁸ and X¹⁰ are CHand X⁹ is CR⁴ where R⁴ is halo (e.g., chloro, bromo, iodo) or alkyl(e.g., methyl). In still a further such variation, R¹ is CH₃ or H, X⁷,X⁸ and X¹⁰ are CH, X⁹ is CR⁴ where R⁴ is halo (e.g., chloro, bromo,iodo) or alkyl (e.g., methyl) and R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) are each hydrogen. In still further such variation,where Q is substituted or unsubstituted piperazinyl, R¹ is other thaniso-propyl. In still a further such variation, where Q is substituted orunsubstituted piperazinyl, R¹ is H, CH₃ or ethyl.

In one variation, the compound is of the formula (A) or (E) where both mand q are 1 and either: (a) at least one of X⁷-X¹⁰ is other than CH or(b) Q is a monocycle selected from a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl andsubstituted or unsubstituted heterocyclyl. In one variation, thecompound is of the formula (A) or (E) where both m and q are 1 andeither: (a) at least one of X⁷-X¹⁰ is other than CH and OCH₃ or (b) Q isa monocycle selected from a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃₋₈ cycloalkyl and substituted or unsubstituted C₃₋₈ cycloalkenyl. In aparticular variation, the compound is of the formula (A) or (E) whereboth m and q are 1 and at least one of X⁷-X¹⁰ is CR⁴ where R⁴ is halo oralkyl. In a still further variation, both m and q are 1; at least one ofX⁷-X¹⁰ is CR⁴ where R⁴ is halo or alkyl; R¹ is alkyl and R^(2a), R^(2b),R^(3a), R^(3b), R^(10a) and R^(10b) are each hydrogen.

In one variation, the compound is of the formula (A) or (E) where atleast one of R^(8a)-R^(8f), where present, is OH. As such, when m is 0and q is 1, at least one of R^(8a), R^(8b), R^(8e) and R^(8f) is OH. Ina further variation, the compound is of the formula (A) or (E) where oneof R^(8a)-R^(8f) is OH and its geminal R^(8(a-f)) moiety is alkyl orperhaloalkyl. In a further such variation, one of m and q is 1 and theother is 0; one of R^(8a)-R^(8f) is OH and its geminal R^(8(a-f)) moietyis alkyl (e.g., methyl, ethyl, cyclopropyl) or perhaloalkyl (e.g.,trifluoroalkyl); X⁷, X⁸ and X¹⁰ are each CH; X⁹ is CR⁴ where R⁴ is alkyl(e.g., methyl) or halo (e.g., chloro, fluoro); and R¹ is alkyl (e.g.,methyl, cyclopropyl).

In one variation, the compound is of the formula (A) or (E) where both mand q are 0 and either:

(a) Q is phenyl and R¹ is ethyl;

(b) Q is 6-methyl-3-pyridyl and R^(8e) and R^(8f) are both H; or

(c) Q is 6-methyl-3-pyridyl and X⁹ is C—R⁴ where R⁴ is hydroxyl, nitro,cyano, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy,carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl. In anothervariation, the compound is of the formula (A) or (E) where both m and qare 0, Q is 6-methyl-3-pyridyl and X⁹ is C—R⁴ where R⁴ is hydrogen oralkyl (e.g., methyl).

In one variation, the compound is of the formula (A) or (E) where atleast one of X⁷-X¹⁰ is N, and at least one of (i)-(iii) applies:

(i) R^(8e) and R^(8f) are both H;

(ii) R¹ is methyl; and

(iii) Q is a substituted or unsubstituted pyridyl.

In one such variation, when Q is a substituted pyridyl, it issubstituted with an alkyl (e.g., methyl, ethyl, isopropyl, n-propyl,cyclopropyl), perhaloalkyl (e.g., trifluoromethyl), substituted alkyl(e.g., hydroxymethyl), carboxyl, carbonylalkoxy (e.g., CO₂CH₃,CO₂CH₂CH₃), substituted amino (e.g., NHCH₃, N(CH₃)₂, NHCH(CH₃)₂),aminoacyl (e.g., NHC(O)CH₃), alkoxy (e.g., OCH₃, OCH₂CH₃), N-oxide(e.g., when the annular nitrogen of the pyridyl is substituted with anoxide), an aryl or heteroaryl fused to the pyridyl, halo (e.g., F, Cl,Br), hydroxyl, N-alkyl (e.g., where the N of the pyridyl is substitutedwith a methyl group or cyclopropyl group), N-perhaloalkyl (e.g., wherethe N of the pyridyl is substituted with a trifluoromethyl group), oxo(which may exist as a tautomer when ortho to the annular nitrogen of thepyridine ring). The substituted pyridyl is preferably substituted withone or two substituents. The substituents may be positioned at anyavailable position on the pyridyl ring. For example, a monosubstituted3-pyridyl may have its substituent at the 2, 4, 5 or 6 positions.

In one variation, the compound is of the formula (A) or (E) where X⁹ isC—R⁴ where R⁴ is —COOH, provided that when R¹ is methyl, Q is other than6-methyl-3-pyridyl or 4-pyridyl. In one variation, the compound is ofthe formula (A) or (E) where one of m and q is 1 and the other is 0, X⁹is C—R⁴ where R⁴ is —COOH, provided that when R¹ is methyl, Q is otherthan 6-methyl-3-pyridyl or 4-pyridyl. In another variation, when X⁹ isC—R⁴ and R¹ is H, Q is other than 6-methyl-3-pyridyl. However, in afurther variation, the methods of the invention, pharmaceuticalcompositions, kits, and purified or isolated forms of the compoundsinclude a compound of the formula (A) or (E) when X⁹ is C—R⁴, R¹ is Hand Q is 6-methyl-3-pyridyl.

In one variation, the compound is of the formula (A) or (E) where Q is atrifluoromethylpyridyl. In a further variation, one of m and q is 1 andthe other is 0, Q is a trifluoromethyl-substituted pyridyl (e.g.,4-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl,6-trifluoromethyl-3-pyridyl) and R¹ is methyl. In still a furthervariation, one of m and q is 1 and the other is 0, Q is atrifluoromethyl-substituted pyridyl (e.g., 4-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl), R¹ is methyland at least one of X⁷-X¹⁰ is other than CH (e.g., when one of X⁷-X¹⁰ isCR⁴ where R⁴ is alkyl (such as methyl, ethyl, isopropyl and tert-butyl),halo (such as chloro and fluoro), carboxyl (COOH) or perhaloalkoxy (suchas —OCF3). In a further variation, one of m and q is 1 and the other is0, R¹ is methyl, X⁹ is CR⁴ where R⁴ is halo or CH₃ and Q is substitutedor unsubstituted 6-trifluoromethyl-3-pyridyl. In a further variation,one of m and q is 1 and the other is 0, R¹ is methyl and X⁹ is CR⁴ whereR⁴ is halo or CH₃ and Q is a substituted 6-trifluoromethyl-3-pyridyl. Instill a further variation, one of m and q is 1 and the other is 0, R¹ ismethyl and X⁹ is CR⁴ where R⁴ is halo or CH₃ and Q is6-trifluoromethyl-3-pyridyl. In another such variation, Q is a6-trifluoromethyl-3-pyridyl substituted with one, two or three moietiesselected from a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, acyl,acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl and aminocarbonylamino. Inanother such variation, Q is a 6-trifluoromethyl-3-pyridyl substitutedwith one, two or three moieties selected from a halo, cyano, nitro,perhaloalkyl and perhaloalkoxy.

In one variation, the compound is of the formula (A) or (E) where R¹ iscyclopropyl, substituted phenyl or carbonylalkoxy, provided that when R¹is carbonylalkoxy, at least one of m and q is 1. In one variation, thecompound is of the formula (A) or (E) where R¹ is cyclopropyl, X⁷, X⁸and X¹⁰ are each CH and X⁹ is CR⁴ where R⁴ is alkyl or halo. In afurther such variation, the compound is of the formula (A) or (E) whereR¹ is cyclopropyl, X⁷, X⁸ and X¹⁰ are each CH; X⁹ is CR⁴ where R⁴ isalkyl or halo and one of m and q is 1 and the other is 0. In anothervariation, the compound is of the formula (A) or (E) where R¹ issubstituted phenyl and Q is 6-methyl-3-pyridyl. In still a furthervariation, the compound is of the formula (A) or (E) where R¹ issubstituted phenyl, Q is 6-methyl-3-pyridyl, X⁷, X⁸ and X¹⁰ are each CH;and X⁹ is CR⁴ where R⁴ is alkyl (e.g., methyl) or halo (e.g., chloro).In one aspect of this variation, one of m and q is 1 and the other is 0.

In one variation, the compound is of the formula (A) or (E) where eitherR^(2a) and R^(2b) or R^(10a) and R^(10b) are taken together with thecarbon to which they are attached to form a carbonyl and at least one ofm and q is 1. In a particular such variation, R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acarbonyl, X⁷, X⁸ and X¹⁰ are each CH; and X⁹ is CR⁴ where R⁴ is alkyl(e.g., methyl) and Q is an unsubstituted phenyl or a substituted pyridyl(e.g., 6-methyl-3-pyridyl and 6-CO₂H-3-pyridyl). In one variation, whenR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a carbonyl, X⁷, X⁸ and X¹⁰ are each CH, X⁹ is CR⁴ whereR⁴ is alkyl (e.g., methyl) and Q is other than 6-CO₂H-3-pyridyl.However, the methods of the invention, pharmaceutical compositions,kits, and purified or isolated forms of the compound include compoundsof this variation, including those in which R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonyl,X⁷, X⁸ and X¹⁰ are each CH, X⁹ is CR⁴ where R⁴ is alkyl (e.g., methyl)and Q is 6-CO₂H-3-pyridyl. In another such variation, R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a carbonyl; X⁷, X⁸ and X¹⁰ are each CH or N and X⁹ is N or CR⁴where R⁴ is alkyl (e.g., methyl).

In one variation, the compound is of the formula (A) or (E) where X⁹ isC—R⁴ where R⁴ is trifluoromethyl and Q is a substituted heteroaryl. Inanother variation, the compound is of the formula (A) or (E) where X⁹ isC—R⁴ where R⁴ is trifluoromethyl, X⁷, X⁸ and X¹⁰ are CH or N; and Q is asubstituted or unsubstituted aryl, substituted heteroaryl or anunsubstituted heterocyclyl moiety. In another variation, the compound isof the formula (A) or (E) where X⁹ is C—R⁴ where R⁴ is trifluoromethyland Q is a substituted heteroaryl. In another variation, the compound isof the formula (A) or (E) where X⁹ is C—R⁴ where R⁴ is trifluoromethyl,X⁷, X⁸ and X¹⁰ are CH or N; one of ma do q is 1 and the other is 0 and Qis a substituted aryl, substituted heteroaryl or an unsubstitutedheterocyclyl moiety.

In one variation, the compound is of the formula (A) or (E) where X⁹ isC—R⁴ where R⁴ is isopropyl or Q is a substituted or unsubstitutedpyrazinyl. In one variation, the compound is of the formula (A) or (E)where X⁹ is C—R⁴ where R⁴ is isopropyl or Q is a substituted orunsubstituted pyrazinyl provided that when Q is 2-pyrazinyl, either (i)R⁹ is other than CR⁴ where R⁴ is CH₃ or (ii) at least one of R^(2a) andR^(2b) is other than hydrogen. In one variation, X⁹ is C—R⁴ where R⁴ isisopropyl; X⁷, X⁸ and X¹⁰ are CH and R¹ is methyl. In another suchvariation, Q is a substituted or unsubstituted pyrazinyl; X⁷, X⁸ and X¹⁰are CH; X⁹ is C—R⁴ where R⁴ is halo (e.g., chloro) or alkyl (e.g.,methyl, ethyl, isopropyl) and R¹ is methyl. In still another suchvariation, Q is a substituted or unsubstituted pyrazinyl; X⁷, X⁸ and X¹⁰are CH; X⁹ is C—R⁴ where R⁴ is halo (e.g., chloro) or C₂-C₄ alkyl (e.g.,ethyl, isopropyl) and R¹ is methyl. In further such variations, one of mand q is 1 and the other is 0.

In one variation, the compound is of the formula (A) or (E) where one ofm and q is 1 and the other is 0, R^(8e) and R^(8f) are both H andeither: (i) Q is a substituted piperazinyl wherein the substitutedpiperazinyl is not 4-(2-methoxyphenyl)-piperazinyl or (ii) Q is asubstituted piperazinyl and at least one of X⁷-X¹⁰ is other than CH. Inanother variation, the compound is of the formula (A) or (E) where oneof m and q is 1 and the other is 0, R^(8e) and R^(8f) are both H andeither: (i) Q is a substituted piperazinyl wherein the substitutedpiperazinyl is not 4-(2-methoxyphenyl)-piperazinyl or (ii) Q is asubstituted piperazinyl and at least one of X⁷-X¹⁰ is other than CH orCR⁴ where R⁴ is OCH₃. In one such variation, one of m and q is 1 and theother is 0; R^(8e) and R^(8e) are both H; Q is a substitutedpiperazinyl; X⁷, X⁸ and X¹⁰ are N or CR⁴ where R⁴ is H or F and X⁹ isCR⁴ where R⁴ is alkyl (e.g., methyl) or halo (e.g., chloro).

In one variation, the compound is of the formula (A) or (E) where Q is6-methyl-3-pyridyl; one of m and q is 1 and the other is 0; R¹ ismethyl; and X⁹ is CR⁴ where R⁴ is iodo or a substituted alkyl. Inanother variation, the compound is of the formula (A) or (E) where Q is6-methyl-3-pyridyl; one of m and q is 1 and the other is 0; R¹ ismethyl; and at least one of R^(8e) and R^(8f) is hydroxyl or alkyl, orR^(8e) and R^(8f) are taken together with the carbon to which they areattached to form a cycloalkyl moiety.

In one variation, the compound is of the formula (A) or (E) where Q is acarboxy substituted pyridyl, provided it is other than6-carboxyl-3-pyridyl, or a carbonylalkoxy substituted pyridyl. However,in a further variation, the methods of the invention, pharmaceuticalcompositions and purified or isolated forms of the compounds include acompound of the formula (A) or (E) where Q is 6-carboxyl-3-pyridyl. Inparticular variations, the compounds further have one or more of thefollowing structural features: R¹ is C₂-C₆ alkyl and X⁹ other than CR⁴where R⁴ is methyl. In one variation, R¹ is C₂-C₆ alkyl, X⁹ other thanCR⁴ where R⁴ is methyl and Q is a carboxy substituted pyridyl or acarbonylalkoxy substituted pyridyl.

In one variation, the compound is of the formula (A) or (E) where Q is asubstituted phenyl and at least one of m and q is 1. In a particularvariation, the compound further has one or more of the followingstructural features: R¹ is methyl or ethyl; X⁷, X⁸ and X¹⁰ are CH; andX⁹ is CR⁴ where R⁴ is halo, alkyl, H or perhaloalkyl (e.g., Cl, I, F,CF₃, methyl). In a further variation, Q is a substituted phenyl; atleast one of m and q is 1 and R¹ is methyl. In yet a further variation,Q is a substituted phenyl; at least one of m and q is 1; R¹ is methyland one or more of (i)-(iii) applies: (i) each of X⁷, X⁸ and X¹⁰ isindependently CR⁴ where R⁴ is hydrogen or halo (e.g., chloro); (ii) X⁹is CR⁴ where R⁴ is hydrogen, alkyl, halo, perhaloalkyl or perhaloalkoxy;and (iii) R^(2a) and R^(2b) are independently hydrogen, methyl orfluoro. Suitable phenyl substituents and substitution patterns include,but are not limited to, those detailed herein, e.g., at paragraph[0140]. In a particular variation, phenyl substituents are those definedas R⁹.

In a particular variation of formula (E), one of m and q is 1 and theother is 0; R¹ is CH₃; X⁷ is N or CR⁴ where R⁴ is hydrogen or chloro; X⁸and X¹⁰ are independently CR⁴ where R⁴ is hydrogen or chloro; X⁹ is CR⁴where R⁴ is alkyl, halo, perhaloalkyl or perhaloalkoxy and Q is asubstituted or unsubstituted aryl, substituted or unsubstitutedcycloalkyl or a substituted or unsubstituted cycloalkenyl. In a furthersuch variation each of R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) andR^(10b) are hydrogen. In one variation, when Q is phenyl then at leastone of X⁷, X⁸ and X¹⁰ is chloro. In another variation, when Q is phenylthen at least one of R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b)and R^(8a)-R^(8f) is other than hydrogen. In still another variation,when Q is phenyl then X⁹ is CR⁴ where R⁴ is chloro, bromo or iodo.

In one variation, the compound is of the formula (A) or (E) where Q isan unsubstituted phenyl and at least one of m and q is 1, provided thatwhen only one of m and q is 1, X⁹ is CR⁴ and X⁷, X⁸ and X¹⁰ are CH, thenR⁴ is other than H. In one such variation, when Q is an unsubstitutedphenyl and only one of m and q is 1, then X⁹ is other than CH. Inparticular variations, the compounds further contain an R¹ that is alkyl(e.g., methyl, ethyl, cyclopropyl) or H. In some of these variations, X⁹is C—R⁴ where R⁴ is hydrogen, alkyl (e.g., methyl) or halo (e.g.,chloro). In others, at least one of X⁷-X¹⁰ is C—R⁴ where R⁴ is halo(e.g., chloro). In still other of these variations, only one of X⁷-X¹⁰is C—R⁴ where R⁴ is halo and the others are each CH. In another suchvariation, when X⁹ is C—R⁴ where R⁴ is hydrogen, then at least one ofX⁷, X⁸ or X¹⁰ is halo (e.g., chloro). In still another variation, Q isan unsubstituted phenyl, at least one of m and q is 1 and at least oneof X⁷-X¹⁰ is N.

In one variation, the compound is of the formula (A) or (E) where any ofR^(8a)-R^(8f), where present, is hydroxyl. In one variation, one ofR^(8e) and R^(8f) is OH. In another variation, when one of R^(8e) andR^(8f) is OH, the other is methyl. In yet another variation, at leastone of R^(8a)-R^(8f), where present, is hydroxyl and one of m and q is 1and the other is 0. In particular variations, the compounds further haveone or more of the following structural features: R¹ is methyl; Q is asubstituted or unsubstituted pyridine (e.g., 3-pyridyl, 4-pyridyl and6-methyl-3-pyridyl); and X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) oralkyl (e.g., methyl). In a particular variation, one of R^(8e) andR^(8f) is OH; X⁷, X⁸ and X¹⁰ are each C—R⁴ where R⁴ is hydrogen; and X⁹is C—R⁴ where R⁴ is alkyl (e.g., methyl) or halo (e.g., chloro andfluoro). In another variation, m is 1, q is 0 and any of R^(8c)-R^(8f)is hydroxyl.

In one variation, the compound is of the formula (A) or (E) where R^(8e)and R^(8f) are taken together with the carbon to which they are attachedto form a carbonyl and either:

(i) Q is (a) a substituted or unsubstituted piperidinyl (which in onevariation, is connected via its annular nitrogen atom to the parentstructure) or (b) an unsubstituted piperizinyl or a piperizinylsubstituted with a branched alkyl group (e.g., isopropyl), or

(ii) X⁹ is CR⁴ where R⁴ is halo (e.g., chloro).

In particular variations, the compounds further have one or more of thefollowing structural features: R¹ is methyl and at least one of m and qis 1.

In another variation, the compound is of the formula (A) or (E) whereR^(8e) and R^(8f) are taken together with the carbon to which they areattached to form a carbonyl; R¹ is methyl or hydrogen and one of m and qis 1 and the other is 0. In another such variation, the compound furtherhas one or more of the following structural features: X⁷, X⁸ and X¹⁰ areeach CH; X⁹ is CR⁴ where R⁴ is halo or alkyl (e.g., methyl); and R^(2a),R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) are each H.

In one variation, the compound is of the formula (A) or (E) where atleast one of X⁷-X¹⁰ is CR⁴ where R⁴ is halo and Q is piperidinyl. In onesuch variation, the compound further has the following structuralfeatures: X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) and Q is1-piperidinyl. In one variation, the compound is of the formula (A) or(E) where Q is a substituted or unsubstituted piperidinyl and at leastone of X⁷-X¹⁰ is either N or CR⁴ where R⁴ is halo. In one variation, thecompound is of the formula (A) or (E) where Q is a substituted orunsubstituted piperidinyl and R^(8e) and R^(8f) are taken together withthe carbon to which they are attached to form a carbonyl.

In one variation, the compound is of the formula (A) or (E) where R^(8e)and R^(8f) are taken together with the carbon to which they are attachedto form a carbonyl, m is 1 and q is 0; and Q is a substituted orunsubstituted heteroaryl or an unsubstituted heterocyclyl; provided thatwhen Q is an unsubstituted piperazinyl, R¹ is other than iso-propyl(e.g., H, CH₃ or ethyl). In one variation, the compound is of theformula (A) or (E) where R^(8e) and R^(8f) are taken together with thecarbon to which they are attached to form a carbonyl, m is 1 and q is 0;and Q is a substituted or unsubstituted heteroaryl or a substitutedunsubstituted heterocyclyl; provided that when Q is a substituted orunsubstituted piperazinyl, R¹ is other than iso-propyl (e.g., H, CH₃ orethyl). In one variation, the compound is of the formula (A) or (E)where R^(8e) and R^(8f) are taken together with the carbon to which theyare attached to form a carbonyl, m is 1 and q is 0; R¹ is hydrogen ofmethyl and Q is an unsubstituted heterocycle. In one such variation, theunsubstituted heterocycle contains no more than one annular heteroatom.

In another variation, the compound is of the formula (A) or (E) whereR^(8e) and R^(8f) are taken together with the carbon to which they areattached to form a carbonyl; R¹ is methyl; Q is a substituted orunsubstituted heteroaryl or an unsubstituted heterocyclyl and one of mand q is 1 and the other is 0. In another such variation, the compoundfurther has one or more of the following structural features: X⁹ is CR⁴where R⁴ is halo or alkyl (e.g., methyl). In another such variation, thecompound further has one or more of the following structural features:X⁷, X⁸ and X¹⁰ are each CH; X⁹ is CR⁴ where R⁴ is halo or alkyl (e.g.,methyl); and R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) areeach H. In one such embodiment, Q is

In another variation, the compound is of the formula (B-1):

wherein:

R⁴ is halo or CH₃;

Q is a substituted or unsubstituted heteroaryl or a substituted orunsubstituted heterocyclyl; and

X⁷, X⁸, X¹⁰, R^(8c) and R^(8d) are as defined in one variation forformula (B) and in another variation for formula (E).

In one variation of B-1, Q is:

In another variation, the invention embraces compounds of the formula(B-2)

wherein:

R⁴ is halo or CH₃; and

each R⁹ is independently a hydrogen, halo, cyano, nitro, perhaloalkyl,or perhaloalkoxy. In another such variation, R⁴ is halo or CH₃ and Q is3Py-6CF₃.

In still another variation, the compound is of the formula (B) or (E),provided that when the compound is of the formula (E), m and 1 and q is0 and provided that at least one of (i)-(iv) applies:

-   -   (i) when X⁷-X¹⁰ are each CR⁴ where R⁴ is hydrogen and R¹ is        methyl or tert-butyl, then Q is other than phenyl or an        unsubstituted pyridyl;    -   (ii) when X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is hydrogen and        X⁹ is CR⁴ where R⁴ is methyl and R¹ is methyl, then Q is other        than phenyl, unsubstituted pyridyl or pyrazinyl;    -   (iii) when X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is hydrogen and        X⁹ is CR⁴ where R⁴ is fluoro or trifluoro and R¹ is methyl, then        Q is other than phenyl, unsubstituted pyridyl and        6-methyl-3-pyridyl; and    -   (iv) when X⁸, X⁹ and X¹⁰ are each CR⁴ where R⁴ is hydrogen and        X⁷ is CR⁴ where R⁴ is fluoro or trifluoro and R¹ is methyl, Q is        other than phenyl or 3-pyridyl.

In another variation, the compound is of the formula (B) or (E) providedthat when the compound is of the formula (E) then m is 1 and q is 0, andprovided that at least one of (i) and (ii) applies:

(i) when X⁸ and X¹⁰ are both CH, one of X⁷ and X⁹ is CR⁴ where R⁴ is For CF₃ and the other is CH, and R¹ is a substituted C₁-C₃ alkyl wherethe substituent is carboxy or carbonylalkoxy, then Q is other thanunsubstituted phenyl, 4-fluorophenyl, and unsubstituted pyridyl; or

(ii) when each of X⁷-X¹⁰ is CH and R¹ is carbonylalkoxy, then Q is otherthan unsubstituted phenyl and unsubstituted pyridyl.

In one variation, the compound is of the formula (A) or (E) where atleast one of X⁷-X¹⁰ is other than CH and Q is pyrrolidinyl. In onevariation, at least one of X⁷-X¹⁰ is C—R⁴ where R⁴ is alkyl and Q ispyrrolidinyl. In a particular variation, X⁹ is CR⁴ where R⁴ is methyl, Qis pyrrolidinyl and X⁹ is CR⁴ where R⁴ is alkyl (e.g., methyl),perhaloalkyl (e.g., CF₃) or halo (e.g., chloro).

In one variation, the compound is of the formula (A) or (E) where Q ismorpholino, and at least one of (i)-(iii) applies:

(i) at least one of m and q is 0;

(ii) at least one of X⁷-X¹⁰ is other than CH; and

(iii) at least one of X⁷-X¹⁰ is CR⁴ where R⁴ is halo.

In a particular variation, Q is morpholino, X⁹ is CR⁴ where R⁴ is chloroand at least one of m and q is 1 and the other is 0. In anothervariation, the compound is of the formula (A) or (E) where Q ismorpholino, R¹ is alkyl and at least one of (i)-(iii) above applies.

In one variation, the compound is of the formula (A) or (E) where Q is aperhaloalkyl substituted pyridyl (e.g., where Q is a 3-pyridylsubstituted at the 5 or 6 position with CF₃). In particular variations,the compounds further have one or more of the following structuralfeatures: at least one of X⁷-X¹⁰ is CR⁴ where each R⁴ is independentlyalkyl (e.g., a C₁-C₃ alkyl such as methyl, ethyl and isopropyl) or halo(e.g., chloro or fluoro); at least one of X⁷, X⁸ or X⁹ is CR⁴ where eachR⁴ is independently alkyl (e.g., a C₁-C₃ alkyl such as methyl, ethyl andisopropyl) or halo (e.g., chloro or fluoro); two of X⁷-X¹⁰ are CR⁴ whereeach R⁴ is independently alkyl (e.g., a C₁-C₃ alkyl such as methyl,ethyl and isopropyl) or halo (e.g., chloro or fluoro), two of X⁷-X¹⁰ areCR⁴ where each R⁴ is independently halo (e.g., chloro or fluoro); X⁸ andX⁹ are both CR⁴ where each R⁴ is independently halo (e.g., chloro orfluoro), which halo substituents may be the same or different (e.g., X⁸is C—F and X⁹ is C—Cl or X⁸ is C—F and X⁹ is C—Cl); and R¹ is methyl andat least one of m and q is 1.

In one variation, the compound is of the formula (A) or (E) where Q is asubstituted or unsubstituted 6-membered heteroaryl having at least twoannular N atoms. In one variation, Q is 5-pyrimidyl or 2-pyrazinyl. Inanother variation, when Q is pyrazinyl, X⁹ is CR⁴ where R⁴ is halo or aC₂-C₄alkyl. In one variation, when Q is a substituted 6-memberedheteroaryl, it is substituted with an alkyl group, e.g., methyl (e.g.,2-methyl-5-pyrimidyl or 5-methyl-2-pyrazinyl). In particular variations,the compounds further have one or more of the following structuralfeatures: R¹ is methyl; X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) oralkyl (e.g., methyl, ethyl, isopropyl); and where one of m and q is 1and the other is 0.

In one variation, the compound is of the formula (A) or (E) where Q iscyclohexyl. In particular variations, the compounds further have one ormore of the following structural features: one of m and q is 1 and theother is 0; at least one of X⁷-X¹⁰ is CR⁴ where R⁴ is halo (e.g., whereX⁸, X⁹ or X¹⁰ is CR⁴ where R⁴ is halo; e.g., where one of X⁷-X¹⁰ is CR⁴where R⁴ is halo and the others are CH); R¹ is methyl; one of X⁷-X¹⁰ isCR⁴ where R⁴ is alkyl (e.g., when R⁴ is methyl; e.g., when X⁹ is C—CH³and X⁷, X⁸ and X¹⁰ are CH).

In one variation, the compound is of the formula (A) or (E) where Q is asubstituted or unsubstituted pyridyl and R¹ is isopropyl.

In one variation, the compound is of the formula (A) or (E) where Q is asubstituted pyridyl provided that (i) the pyridyl substituent is otherthan methyl and (ii) when one of m and q is 1 and the other is 0, X⁹ isCR⁴ where R⁴ is methyl and R¹ is CH₃, the pyridyl substituent is otherthan COOH. However, in a further variation, the methods of theinvention, pharmaceutical compositions and purified or isolated forms ofthe compounds include a compound of the formula (A) or (E) when Q is asubstituted pyridyl and (i) the substituent is methyl and (ii) when oneof m and q is 1 and the other is 0, X⁹ is CR⁴ where R⁴ is methyl and R¹is CH₃, the substituent is COOH. In a particular variation, Q is apyridyl substituted with at least one moiety selected from ethyl, propyl(n-propyl or isopropyl), halo (e.g., chloro) and hydroxymethyl. Inanother particular variation, Q is a pyridyl substituted with at leastone moiety selected from ethyl, propyl (n-propyl or isopropyl), halo(e.g., chloro), perhaloalkyl (e.g., CF₃) and hydroxymethyl. Inparticular variations, the compounds further have one or more of thefollowing structural features: R¹ is methyl and X⁹ is CR⁴ where R⁴ ismethyl or chloro (and in a particular variation, X⁷, X⁸ and X¹⁰ are CH);and m and q is 1 and the other is 0.

In one variation, the compound is of the formula (A) or (E) where Q ismethylpyridyl (e.g., 6-methyl-3-pyridyl); m and q are 0 and either: (i)at least one of X⁷-X⁹ is CR⁴ where R⁴ is alkyl (e.g., methyl) or (ii)both of R^(8e) and R^(8e) are H. In particular variations, the compoundsfurther have one or more of the following structural features: X⁹ is CR⁴where R⁴ is methyl and X⁷, X⁸ and X¹⁰ are CH and R¹ is methyl or ethyl.

In one variation, the compound is of the formula (A) or (E) where atleast one of X⁸ and X¹⁰ is CR⁴ where R⁴ is F. In a particular variation,X⁸ is CR⁴ where R⁴ is F; X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) orhydrogen and R¹ is alkyl (e.g., methyl). In another variation, X¹⁰ isCR⁴ where R⁴ is F and one of m and q is 1 and the other is 0. In still afurther variation, at least one of X⁸ and X¹⁰ is CR⁴ where R⁴ is F; oneof m and q is 1 and the other is 0 and Q is 6-trifluoromethyl-3-pyridylor 6-methyl-3-pyridyl.

In one variation, the compound is of the formula (A) or (E) where Q is6-methyl-3-pyridyl; R¹ is methyl and one of X⁷-X¹⁰ is C—F. In aparticular variation, Q is 6-methyl-3-pyridyl; R¹ is methyl; X⁸ is C—Fand X⁹ is CR⁴ where R⁴ is halo (e.g., chloro).

In one variation, the compound is of the formula (A) or (E) where Q is5-methyl-3-pyridyl. In particular variations, the compounds further haveone or more of the following structural features: one of m and q is 1and the other is 0; R¹ is methyl and X⁹ is CR⁴ where R⁴ is alkyl (e.g.,methyl).

In one variation, the compound is of the formula (A) or (E) where Q isan unsubstituted pyridyl (e.g., 2-pyridyl) and both m and q are 1. Inparticular variations, the compounds further have one or more of thefollowing structural features: R¹ is methyl; X⁹ is CR⁴ where R⁴ is alkyl(e.g., methyl).

In one variation, the compound is of the formula (A) or (E) where Q isan unsubstituted 3-pyridyl; one of m and q is 1 and the other is 0 andX⁹ is CR⁴ where R⁴ is alkyl (e.g., methyl). In one variation, R¹ ismethyl or carbonylalkoxy provided that when R¹ is methyl, then at leastone of R^(2a), R^(2b), R^(3a), R^(3a), R^(8a)-R^(8f) and R^(10a),R^(10b) is other than hydrogen. In particular variations, the compoundsfurther have one or more of the following structural features: R¹ ismethyl; each of R^(2a), R^(2b), R^(3a), R^(3a), R^(8a)-R^(8f) andR^(10a), R^(10b) are H.

In one variation, the compound is of the formula (A) or (E) where Q isan unsubstituted 2-pyridyl; one of m and q is 1 and the other is 0 andeither: (i) R¹ is ethyl or (ii) at least one of X⁷-X⁹ is CR⁴ wherein R⁴is other than H (in a particular variation, X⁹ is CR⁴ where R⁴ is alkyl(e.g., methyl) or halo (e.g., chloro)). In particular variations, thecompounds further have one of the following structural features: R¹ isethyl and X⁹ is CR⁴ where R⁴ is CH₃ or R¹ is ethyl and each of X⁷-X⁹ isCR⁴.

In one variation, the compound is of the formula (A) or (E) where Q is4-pyridyl; one of m and q is 1 and the other is 0; and R¹ is ethyl. Inparticular variations, the compounds further have one of the followingstructural features: X⁹ is CR⁴ where R⁴ is H or alkyl and X⁷, X⁸ and X¹⁰are H.

In yet another variation, the compound is of the formula (A) or (E)where at least one of X⁷-X¹⁰ is N and either (i) R¹ is methyl or (ii)R^(8e) and R^(8f) are both hydrogen. In one such variation, only one ofX⁷-X¹⁰ is N, R¹ is methyl and the X⁷-X¹⁰ that are not N are CR⁴ where R⁴is hydrogen, methyl or trifluoromethyl. In another variation, thecompound is of the formula (A) or (E) where two of X⁷-X¹⁰ are N (e.g.,X⁷ and X¹⁰ are both N or X⁷ and X⁸ are both N).

In still another variation, the compound is of the formula (A) or (E)where q is 0, m is 1, R^(8e) and R^(8f) are taken together to form acarbonyl, and at least one of (i)-(vi) applies: (i) Q is a substitutedor unsubstituted heteroaryl or an unsubstituted heterocyclyl, (ii) R¹ isCH₃ or H, (iii) X⁹ is halo or CH₃ provided that when X⁹ is CH₃, R¹ is Hor CH₃, (iv) X⁷ and X⁸ are both CR⁴ (e.g. CH) and R¹ is H or CH₃, (v)each X⁷-X¹⁰ is CH and R¹ is H or CH₃, and (vi) each X⁷-X¹⁰ is CH and Qis a substituted or unsubstituted heteroaryl or an unsubstitutedheterocyclyl. In another variation, the compound is of formula (A) or(E) where q is 0, m is 1, R^(8e) and R^(8f) are taken together to form acarbonyl, and Q is an unsubstituted or substituted piperidinyl. In aparticular such variation, Q is an unsubstituted piperidinyl, X⁹ is haloor CH₃ and R¹ is CH₃ or H.

The invention also embraces a compound of the formula (B):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano or nitro or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl,C₁-C₈ alkyl or is taken together with the carbon to which it is attachedand a geminal R₈ to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or a unsubstitutedheterocyclyl;

provided that (i) the compound is other than any of compounds 72x, 125x,126x, 127x, 128x, 129x, 130x, 131x, 132x, 133x, 134x, 135x, 136x, 137x,138x, 139x, 140x, 141x, 142x, 143x, 144x, 145x, 146x, 148x, 149x, 150x,151x, 152x, 155x, 156x, 157x, 158x, 159x, 160x, 161x, 162x, 163x, 164x,165x, 166x, 167x, 168x, 169x, 170x, 171x, 172x, 173x, 174x, 175x, 176x,177x, 178x, 179x, 180x, 181x, 182x, 183x, 184x, 185x, 186x, 187x, 188x,189x, 190x, 191x, 192x, 193x, 194x, 195x, 196x, 197x, 198x, 199x, 200x,201x, 203x, 204x, 222x, 223x, 224x, 225x, 226x, 227x, 228x, 229x, 233x,234x, 235x, 237x, 241x, 243x, 244x, 245x, 246x, 247x, 248x, 249x, 250x,251x, 252x, 253x, 254x, 255x, 256x, 257x and 258x or a salt thereof and(ii) the compound is other than any of compounds 229H, 230, 241, 255,256, 262 and 274 or a salt thereof. In another variation, the compoundsof the invention, and methods of using the compounds and administeringthe compounds as detailed herein, encompass any of the compounds offormula B, including those listed in Table 1 or a salt thereof andcompounds 229H, 230, 241, 255, 256, 262 and 274, or a salt thereof.

In one variation, the compound is of the formula (B) wherein thecompound further is a type 1 compound. In another variation, thecompound is of the formula (B) wherein the compound further is a type 2compound. In yet another variation, the compound is of the formula (B)wherein the compound further is a type 3 compound. In a furthervariation, the compound is of the formula (B) wherein the compoundfurther is a type 4 compound.

In one variation, the compound is of formula (B) provided that (i) Q isother than unsubstituted pyridyl or 4-substituted-1-piperazinyl; (ii)when Q is substituted pyridyl, it is substituted with at least one groupthat is other than methyl; and (iii) the compound is other than any ofcompounds 176x, 177x, 178x, 179x, 204x, 243x, 244x, 245x, 246x, 247x and251x. In a further variation, the compound is of formula (B) providedthat (i) Q is other than unsubstituted pyridyl or4-substituted-1-piperazinyl; (ii) when Q is substituted pyridyl, it issubstituted with at least one group that is other than methyl; (iii)when Q is pyrrolidinyl, piperidinyl, azepinyl, phenyl or substitutedpiperazinyl, at least one of X⁷, X⁸, X⁹ and X¹⁰ is other than CH; and(iv) the compound is other than any of compounds 176x, 178x, 243x, 244x,245x, 246x, 247x and 251x. In a further variation, the compound is offormula (B) provided that (i) at least one of R^(8c), R^(8d), R^(8e) andR^(8f) is other than H; and (ii) R^(8e) and R^(8f) are not takentogether with the carbon to which they are attached to form a carbonyl.

In another variation, the compound is of the formula B where Q is asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, or substituted or a unsubstitutedheterocyclyl, provided that: (i) when Q is substituted piperazin-1-yl,it is other than 4-(2-methoxyphenyl)piperazin-1-yl; (ii) when Q ispyrrolidin-1-yl, piperidin-1-yl, or azepan-1-yl, it is substitutedpyrrolidin-1-yl, piperidin-1-yl, or azepan-1-yl or (iii) the compound isnot2-methyl-5-(2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2-methyl-5-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2,8-dimethyl-5-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;or5-(2-(azepan-1-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,or a salt or solvate thereof. In one variation, the compound is of theformula B or any variation thereof detailed herein, where Q is acarbocycle, such as a 5, 6 or 7 membered carbocycle. In one variation,the compound is of the formula B or any variation thereof detailedherein, where Q is a heterocycle, such as a 3, 4, 5, 6 or 7 memberedcarbocycle. In one variation, the compound is of the formula B or anyvariation thereof detailed herein, where Q is a heterocycle, such as a5, 6 or 7 membered heterocycle. In one variation, the compound is of theformula B or any variation thereof detailed herein, where Q is aheterocycle, such as a 3, 4, 5, 6 or 7 membered heterocycle.

In another variation, the compound is of the formula B where Q issubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, provided that (i) at least one of X⁷-X¹⁰ is other than CHand at least one of (ii)-(viii) applies: (ii) when Q is2-methylpyridin-3-yl or an unsubstituted moiety selected from phenyl andpyridin-3-yl, R¹ is not methyl and provided that the compound is otherthan 125x, 177x, 184x and 237x (iii) when Q is unsubstitutedpyridin-2-yl, R¹ is other than H or an unsubstituted moiety selectedfrom methyl, propyl, and butyl and provided that the compound is otherthan 180x-183x; (iv) when Q is unsubstituted pyridin-4-yl, R¹ is otherthan H or an unsubstituted moiety selected from methyl, propyl, butyl,phenethyl, and benzoyl provided the compound is other than 185x-241x;(v) when Q is 6-methylpyridin-3-yl, R¹ is other than H or anunsubstituted moiety selected from methyl, ethyl, propyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, cyclohexyl, heptyl, benzyl, andphenyl; (vi) at least one of X⁷-X¹⁰ is N; (vii) at least one ofR^(8c)-R^(8f) is other than H; and (viii) at least one of R^(2a),R^(2b), R^(3a), R^(3b), R^(10a), or R^(10b) is other than H, or a saltor solvate thereof. In another variation, the compound is of the formulaB where Q is a substituted or unsubstituted heteroaryl, such as a 5, 6or 7 membered heteroaryl, provided that at least one of provisions(ii)-(viii) above applies. In one variation, the compound is of theformula B where Q is a substituted or unsubstituted aryl, such as a 5, 6or 7 membered aryl, provided that: (a) when Q is an unsubstituted phenylmoiety, R¹ is not methyl provided the compound is not 177x; (b) at leastone of X⁷-X¹⁰ is N; (c) at least one of R^(8c)-R^(8f) is other than H;or (d) at least one of R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), orR^(10b) is other than H, or a salt or solvate thereof.

In another variation, the invention embraces compounds of the formula(B) where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(8c)-R^(8f),R^(10a), R^(10b), m and q a are as defined in one variation in formula(I) and in another variation in formula (E) and Q is substituted phenylor a substituted or unsubstituted pyrrolyl, or a pharmaceuticallyacceptable salt thereof. In one variation of formula (B), X⁹ is C—R⁴where R⁴ is halo or H. In another variation of formula (B), R¹ is alkyl,such as a C₁-C₈ alkyl, e.g., methyl. Compounds of formula (B) where X⁹is C—R⁴ and where R⁴ is halo (e.g., chloro) or H and where R¹ is methylare embraced. In another variation of formula (B), each of X⁷, X⁸ andX¹⁰ is CH; X⁹ is C—R⁴ where R⁴ is halo or H and R^(2a), R^(2b), R^(3a),R^(3b), R^(8a)-R^(8f), R^(10a), R^(10b) are independently H or alkyl,e.g., methyl. In one variation, the invention embraces compounds of theformula (B) where X⁹ is C—R⁴ where R⁴ is chloro; X⁷ is N or C—R⁴ whereR⁴ is hydrogen or halo; X⁸ and X¹⁰ are independently C—R⁴ where R⁴ ishydrogen or fluoro and at least one of (i)-(iii) applies: (i) at leastone of R^(8e) and R^(8f) is hydroxyl, C₁-C₈alkyl, C₁-C₈perhaloalkyl oris taken together with the carbon to which it is attached and a geminalR^(8(e-f)) to form a cycloalkyl moiety or a carbonyl moiety; (ii) atleast one of R^(8e) and R^(8f) is C₁-C₈alkyl; (iii) Q is a substitutedor unsubstituted aryl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₃-C₈cycloalkenyl or a substituted orunsubstituted heterocyclyl. In a particular variation, the inventionembraces compounds of the formula (B) where X⁹ is C—R⁴ where R⁴ ischloro; X⁷ is N or C—R⁴ where R⁴ is hydrogen or halo; X⁸ and X¹⁰ areindependently C—R⁴ where R⁴ is hydrogen or fluoro and Q is a substitutedor unsubstituted heteroaryl, provided that when Q is an unsubstitutedheteroaryl it is other than pyridyl and when Q is a substitutedheteroaryl, it is other than 6-methyl-3-pyridyl.

In any variation of formula (B) detailed herein, in one variation Q is aphenyl substituted with an alkyl, perhaloalkyl, halo, hydroxyl or alkoxymoiety. In another variation, Q is a phenyl substituted with two orthree moieties selected from methyl, perhaloalkyl, halo, hydroxyl andalkoxy. Particular phenyl substituents for Q are methyl,trifluoromethyl, fluoro, chloro, hydroxyl, methoxy, ethoxy andisopropoxy. When Q is a phenyl substituted with two or three moieties,the moieties may be the same or different. For example, Q may bedifluorophenyl, dichlorophenyl, dimethoxyphenyl,di(trifluoromethyl)phenyl, trifluorophenyl, (fluoro)(chloro)phenyl,(fluoro)(trifluoromethyl)phenyl, (chloro)(trifluoromethyl)phenyl or(fluoro)(methoxy)phenyl.

When a compound of the formula (B) has a Q that is a substituted phenyl,the substituent or substituents may be positioned at any availablephenyl ring position. For example, singly-substituted phenyl groups maybe substituted at the ortho, meta or para-position of the phenyl group.Any available phenyl ring substitution pattern is suitable for di- ortri-substituted phenyl groups (e.g., at the ortho and para positions, attwo ortho positions, at two meta positions, at the meta and parapositions, at the ortho, meta and para positions, at two ortho and thepara position, at two ortho and a meta position, or at two meta and apara or ortho position). In any variation of formula (B) detailedherein, in one variation Q is an unsubstituted pyrrolyl or a pyrrolylsubstituted with an alkyl moiety (e.g., methyl, ethyl or propyl,including isopropyl). In one variation, the unsubstituted pyrrolyl or apyrrolyl substituted with a single moiety is attached to the carbonbearing R^(8e) and R^(8f) via the 1, 2 or 3-positions of theunsubstituted or mono-substituted pyrrolyl moiety.

In another variation, the compound is of the formula (B) and Q iseither:

(i) 4-trifluoromethyl-3-pyridyl;

(ii) unsubstituted phenyl, provided that at least one of X⁷-X¹⁰ is otherthan CH; or

(iii) Q is piperidinyl and R^(8e) and R^(8f) are taken together with thecarbon to which they are attached to form a carbonyl.

All variations referring to Formula (A) and/or Formula (E), whereapplicable, may apply equally to formula B the same as if each and everyvariation were specifically and individually listed. Likewise, allvariations referring to Formula (A) and/or Formula (E), whereapplicable, may apply to any other formulae detailed herein, the same asif each and every variations were specifically and individually listed.

In another variation, the compound is of the formula (E) or (B), where:

m is 1 and q is 0 (when the variation refers to formula (E));

R¹ is CH₃ or ethyl;

each of R^(8c) and R^(8d) are both H;

R^(8e) and R^(8f) are independently H, OH or CH₃;

X⁷ is CH; X⁸ is CH or C-halo; X¹⁰ is CH or C-halo;

X⁹ is CR⁴ where R⁴ is halo, CH₃, CF₃ or ethyl; and

Q is substituted or unsubstituted phenyl or substituted or unsubstitutedpyridyl, provided that either:

-   -   (i) when R¹ is CH₃, both R^(8e) and R^(8f) and H, X⁹ is CR⁴        where R⁴ is F or CF₃ and Q is phenyl, the compound is other than        244x and 245x; or    -   (ii) when R¹ is CH₃, R^(8e) and R^(8f) are both H; and Q is        2-pyridyl, 2-methyl-3-pyridyl or 6-methyl-3-pyridyl, the        compound is other than 181x, 250x, 254x, 125x, 131x, 132x, 133x,        134x, 140x, 141x, 148x, 168x, 169x, 170x, 171x, 172x, 173x,        174x, 175x and 255x.        In one such variation, Q is a phenyl substituted with one, two        or three moieties selected from halo, C₁₋₄ alkyl, —O—C₁₋₄ alkyl,        perhaloalkyl and perhaloalkoxy. In one variation, Q is a phenyl        substituted with one, two or three moieties selected from F, Cl,        I, Br, methyl, ethyl, propyl, CF₃, OMe, OEt, and O—CH(CH₃)₂. In        another such variation, Q is 2-pyridyl, 3-pyridyl or 4-pyridyl,        each of which may be substituted with one, two or three moieties        selected from a C₁₋₄ alkyl, halo, perhaloalkyl, or        perhaloalkoxy. In one variation, Q is a pyridyl substituted with        one, two or three moieties selected from F, Cl, I, Br, methyl,        ethyl, propyl, iso-propyl and CF₃.

The invention also embraces compounds of the formula (C):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano or nitro or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl or is taken together with the carbon to whichit is attached and a geminal R₈ to form a cycloalkyl moiety or acarbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or a unsubstitutedheterocyclyl, provided that the compound is other than any of compounds202x, 205x, 206x, 207x, 208x, 209x, 210x, 211x, 212x, 213x, 214x and221x, or a salt thereof. In another variation, the compounds of theinvention, and methods of using the compounds detailed herein, encompassany of the compounds of formula C, including those listed in Table 1,such as compounds 202x, 205x, 206x, 207x, 208x, 209x, 210x, 211x, 212x,213x, 214x and 221x, or a salt thereof.

In one variation, the compound is of formula (C) provided that (i) whenQ is a substituted piperazinyl, at least one of X⁷, X⁸, X⁹ and X¹⁰ isother than CH; and (ii) the compound is other than any of compounds202x, 214x and 221x.

In another variation, the compound is of the formula C where Q is asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, or substituted or a unsubstitutedheterocyclyl, provided that: (i) when Q is4-(2-methoxyphenyl)piperazin-1-yl, R¹ is not H, benzyl, methyl, acetyl,or benzoyl; or (ii) when Q is 4-benzylpiperazin-1-yl, R¹ is not methyl;or (iii) when Q is 4-methylpiperazin-1-yl, R¹ is not methyl, benzyl, orphenethyl; or (iv) the compound is not 1H-Pyrido[4,3-b]indole,2,3,4,5-tetrahydro-2-methyl-5-[3-(4-morpholinyl)propyl]-, or a salt orsolvate thereof. In one variation, the compound is of the formula Cwhere Q is a carbocycle, such as a 5, 6 or 7 membered carbocycle. Inanother variation, the compound is of the formula C where Q is aheterocycle, such as a 5, 6 or 7 membered heterocycle.

In another variation, the compound is of the formula C where Q is asubstituted or unsubstituted aryl, such as a 5, 6 or 7 membered arylgroup. In another variation, the compound is of the formula C where Q isa substituted or unsubstituted heteroaryl, such as a 5, 6 or 7 memberedheteroaryl group.

The invention also embraces compounds of the formula D:

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano or nitro or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8e) and R^(8f) is independently H, hydroxyl, C₁-C₈ alkyl or istaken together with the carbon to which it is attached and a geminal R₈to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or a unsubstitutedheterocyclyl;

provided that the compound is other than any of compounds 1x, 2x, 3x,4x, 5x, 6x, 7x, 8x, 9x, 10x, 11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x,19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x,33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x,47x, 48x, 49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x,61x, 62x, 65x, 66x, 67x, 68x, 69x, 70x, 71x, 73x, 74x, 77x, 78x, 79x,80x, 81x, 82x, 83x, 84x, 85x, 88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x,96x, 97x, 98x, 100x, 101x, 102x, 103x, 104x, 105x, 106x, 107x, 109x,110x, 111x, 113x, 114x, 115x, 116x, 117x, 118x, 119x, 120x, 121x, 122x,123x, 124x, 216x, 217x, 218x, 219x, 220x, 230x, 231x, 232x, 236x, 238x,239x, 240x, 259x, 260x, 261x, 262x, 263x, 264x, 265x, 266x, 267x, 268x,269x, 270x, 271x, 272x, 273x, 274x, 275x, 276x, 277x, 278x, 279x, 280x,281x, 282x, 283x, 284x, 285x, 286x, 287x, 288x, 289x, 290x, 291x, 292x,293x, 294x, 295x, 296x, 297x, 298x, 299x, 300x, 301x, 302x, 303x, 304x,305x, 306x, 307x, 308x, 309x, 310x, 311x, 312x, 313x, 314x, 315x, 316x,317x and 318x or a salt thereof. In another variation, the compounds ofthe invention, and methods of using the compounds detailed herein,encompass any of the compounds of formula D, including those listed inTable 1 and Table 1A, such as compounds 1x-62x, 65x-71x, 73x, 74x,77x-85x, 88x-98x, 100x-107x, 109x-111x, 113x-124x, 216x-220x, 230x-232x,236x, 238x-240x, 259x-295x and 296x-318x, or a salt thereof. In onevariation, the compound is of the formula D where Q is a carbocycle or aheterocycle, such as a 5, 6 or 7 membered carbocycle or heterocycle.

In still another variation, the compound is of the formula D where Q issubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl provided that:

(i) when Q is a substituted or unsubstituted heteroaryl the compound isnot Piperidine,1-[[2-cyclopentyl-2,3,4,5-tetrahydro-5-[(2-methyl-4-thiazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-;Piperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-[(2-methyl-4-thiazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-;2-Furancarboxylic acid,5-[[2-cyclopentyl-1,2,3,4-tetrahydro-8-[(4-methyl-1-piperidinyl)carbonyl]-5H-pyrido[4,3-b]indol-5-yl]methyl]-;Piperidine,1-[[2-cyclopentyl-2,3,4,5-tetrahydro-5-[(5-methyl-4-isoxazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-4-methyl-;Piperidine,4-methyl-1-[[2,3,4,5-tetrahydro-5-[(5-methyl-4-isoxazolyl)methyl]-1H-pyrido[4,3-b]indol-8-yl]carbonyl]-;8-chloro-2-methyl-5-(1-(6-methylpyridin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-bromo-2-methyl-5-(1-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-chloro-2-methyl-5-(1-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and

(ii) when Q is a substituted or unsubstituted aryl, (a) it is other than5-(2,4-dimethylbenzyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;5-(4-chlorobenzyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;7-chloro-5-(4-chlorobenzyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-chloro-5-(4-chlorobenzyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-fluoro-5-(4-fluorobenzyl)-2-(2-(pyridin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;(5-(4-hydroxybenzyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)(4-hydroxyphenyl)methanone;and8-chloro-5-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;or (b) it is other than an unsubstituted phenyl; and

(iii) when X⁹ is CR⁴, R⁴ is other than 4-methylpiperidine-1-carbonyl,4-methoxypiperidine-1-carbonyl, 4-ethoxypiperidine-1-carbonyl; or

or a salt or solvate thereof.

In one variation, the compound is of the formula (E) or (D) providedthat when the compound is of the formula (E), both m and q are 0, and atleast one of (i)-(vii) applies:

(i) when X⁸ and X¹⁰ are both CH, X⁷ is CR⁴ where R⁴ is F, CF₃ orcarbonylalkoxy, X⁹ is CR⁴ where R⁴ is H, methyl, fluoro, orcarbonylalkoxy, and R¹ is H or substituted or unsubstituted C₁-C₅alkyl,then Q is other than unsubstituted phenyl, 4-fluorophenyl,4-ethoxycarbonylphenyl and unsubstituted pyridyl;

(ii) when X⁸ and X¹⁰ are both CH, X⁷ is CR⁴ where R⁴ is F, CF₃ orcarbonylalkoxy, X⁹ is CR⁴ where R⁴ is H, methyl, fluoro, orcarbonylalkoxy, and R¹ is carbonylalkoxy, then Q is other than phenyl,4-fluorophenyl and unsubstituted pyridyl;

(iii) when each X⁷-X¹⁰ is CH and R¹ is carbonylalkoxy, then Q is otherthan phenyl and unsubstituted pyridyl;

(iv) when X⁸ and X¹⁰ are both CH, one of X⁷ and X⁹ is CR⁴ where R⁴ iffluoro, CF₃, carboxyl or carbonylalkoxy and the other is CH, R¹ is H,methyl, substituted C₁-C₂alkyl or carbonylalkoxy, then Q is other thanphenyl, 4-fluorophenyl and unsubstituted pyridyl;

(v) when each of X⁷-X¹⁰ is CH and R¹ is methyl or butyl, then Q is otherthan phenyl, 4-fluorophenyl and unsubstituted pyridyl;

(vi) when X⁷, X⁸ and X¹⁰ are each CH; X⁹ is CR⁴ where R⁴ is fluoro,methyl or CF₃ and R¹ is methyl, then Q is other than phenyl, substitutedphenyl, unsubstituted pyridyl, 1,2,5,6-tetrahydropyridin-3-yl and2-thiophenyl; and

(vii) when each of X⁸-X¹⁰ is CH, X⁷ is CR⁴ where R⁴ is fluoro or CF₃,and R¹ is methyl, then Q is other than phenyl and unsubstituted pyridyl.

In one variation, a compound of the invention is of the Formula (I)where: R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl or substitutedor unsubstituted aryl; each R^(2a) and R^(2b) is independently H,methyl, fluoro or R^(2a) and R^(2b) are taken together to form acarbonyl moiety; each R^(3a) and R^(3b) is independently H or fluoro;and each R^(10a) and R^(10b) is independently H, halo, hydroxyl ormethyl or R^(10a) and R^(10b) are taken together to form a carbonyl.This variation of Formula (I) is referred to herein as formula “(Ia)”.In one variation, the compound is of the Formula (Ia), provided that thecompound is other than a compound in Table 1 or salt thereof. In anothervariation, the compound is of the formula Ia, provided that the compoundis other than any of compounds 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x,11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x,25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x,39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 52x,53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 65x, 66x, 67x, 68x,69x, 71x, 72x, 73x, 74x, 77x, 78x, 80x, 81x, 82x, 83x, 84x, 85x, 89x,90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 100x, 101x, 102x, 103x,104x, 105x, 106x, 107x, 109x, 110x, 111x, 113x, 114x, 115x, 116x, 117x,118x, 119x, 120x, 121x, 122x, 123x, 124x, 125x, 126x, 127x, 128x, 129x,130x, 131x, 132x, 133x, 134x, 135x, 136x, 137x, 138x, 139x, 140x, 141x,142x, 143x, 144x, 145x, 146x, 148x, 149x, 150x, 151x, 152x, 155x, 157x,158x, 159x, 160x, 161x, 162x, 163x, 164x, 165x, 166x, 167x, 168x, 169x,170x, 171x, 172x, 173x, 174x, 175x, 176x, 177x, 178x, 179x, 181x, 182x,183x, 184x, 185x, 186x, 187x, 188x, 189x, 190x, 191x, 192x, 193x, 194x,195x, 196x, 197x, 198x, 199x, 200x, 201x, 202x, 203x, 204x, 205x, 206x,207x, 208x, 209x, 210x, 211x, 212x, 213x, 214x, 219x, 220x, 221x, 222x,223x, 224x, 225x, 226x, 227x, 228x, 229x, 230x, 231x, 232x, 233x, 234x,235x, 236x, 237x, 238x, 239x, 243x, 244x, 245x, 246x, 247x, 248x, 249x,250x, 251x, 252x, 253x, 254x, 255x, 256x, 257x, 258x, 259x, 260x, 261x,262x, 263x, 264x, 265x, 266x, 267x, 268x, 269x, 270x, 271x, 272x, 273x,274x, 275x, 276x, 277x, 278x, 279x, 280x, 281x, 282x, 283x, 284x, 285x,286x, 287x, 288x, 289x, 290x, 291x, 292x, 293x, 294x and 295x or saltthereof. In another variation, the compounds of the invention, andmethods of using the compounds detailed herein, encompass any of thecompounds of formula Ia, including those listed in Table 1 or a saltthereof. All variations referring to Formula (I), where applicable, mayapply equally to any of formula A-F the same as if each and everyvariation were specifically and individually listed. Similarly, allvariations referring to formula (I), where applicable, apply equally toall formulations and variations detailed herein.

In a particular embodiment, the compound is of the Formula (I) or Iawhere X⁷, X⁸, X⁹ and X¹⁰ are CR⁴. In another embodiment, the compound isof the Formula (I) or Ia where at least one of X⁷, X⁸, X⁹ and X¹⁰ is N.Another variation provides a compound of the Formula (I) or Ia where atleast two of X⁷, X⁸, X⁹ and X¹⁰ are N. A further variation provides acompound of the Formula (I) or Ia where twi of X⁷, X⁸, X⁹ and X¹⁰ are Nand two of X⁷, X⁸, X⁹ and X¹⁰ are CR⁴. A compound of the Formula (I) orIa where one of X⁷, X⁸, X⁹ and X¹⁰ is N and three of X⁷, X⁸, X⁹ and X¹⁰are CR⁴ is also embraced by this invention.

In another variation, a compound of the invention is of the Formula (I)or Ia where X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide an aromaticmoiety selected from the following structures:

where each R⁴ is as defined for Formula (I) or Ia; or in a particularvariation, where each R⁴ is independently hydroxyl, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino oracyl; or in still a further variation, where R⁴ is independently halo,unsubstituted C₁-C₄ alkyl or C₁-C₄ perhaloalkyl. In one variation, R⁴ ishydroxyl, carboxyl, methyl, —CF₃, chloro, —OCF₃, iso-propyl, ethyl,tert-butyl, —CH₂OH, bromo, iodo, fluoro, 3-pyridyl or —CH₂CH₂CH₂NH₂. Inone variation, R⁴ is other than hydrogen.

In still a further variation, a compound of the invention is of theFormula (I) or Ia where X⁷, X⁸, X⁹ and X¹⁰ are taken together provide anaromatic moiety selected from the following structures:

wherein R⁴ is as defined in Formula (I); or in a particular variation,where R⁴ is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,alkylsulfonylamino or acyl; or in still a further variation, where eachR⁴ is independently halo, unsubstituted C₁-C₄ alkyl or C₁-C₄perhaloalkyl. In still another variation, R⁴ is H, hydroxyl, carboxyl,methyl, —CF₃, chloro, —OCF₃, iso-propyl, ethyl, tert-butyl, —CH₂OH,bromo, iodo, fluoro, 3-pyridyl or —CH₂CH₂CH₂NH₂.

In another variation, a compound of the invention is of the Formula (I)or Ia or any variation herein, where X⁷, X⁸, X⁹ and X¹⁰ are takentogether to form

where R⁴ is as defined in any variation herein, including where R⁴ is H,hydroxyl, carboxyl, methyl, —CF₃, chloro, —OCF₃, iso-propyl, ethyl,tert-butyl, —CH₂OH, bromo, iodo, fluoro, 3-pyridyl or —CH₂CH₂CH₂NH₂.

In another embodiment, a compound of the invention is of the Formula(I), wherein X⁷-X¹⁰ are as defined in Formula (I) or as detailed in anyvariation herein, where R¹ is H, substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl. In afurther embodiment, a compound of the invention is of the Formula (I),wherein X⁷-X¹⁰ are as defined in Formula (I) or as detailed in anyvariation herein, where R¹ is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl or substituted or unsubstituted aryl. In a particularvariation, a compound of the invention is of the Formula (I), whereinX⁷-X¹⁰ are as defined in Formula (I) or as detailed in any variationherein, where R¹ is methyl, ethyl, cyclopropyl, propylate,trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl,propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl. In another variation of anyformula or substructure herein, R¹ is H, carboxyl, propyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, hydroxymethyl,3-amino-propyl, formyl, n-butyl, phenyl, or any of

In another variation, the compound of the invention is of the Formula(I), where X⁷-X¹⁰ and R¹ are as defined in Formula (I) or as detailed inany variation herein, where R^(2a) and R^(2b) are independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro or R^(2a)and R^(2b) are taken together to form a carbonyl moiety and each R^(3a)and R^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano or nitro. In another variation, the compound of theinvention is of the Formula (I), where X⁷-X¹⁰ and R¹ are as defined inFormula (I) or as detailed in any variation herein, where each R^(2a)and R^(2b) is independently H, unsubstituted C₁-C₈ alkyl, halo or R^(2a)and R^(2b) are taken together to form a carbonyl moiety and each R^(3a)and R^(3b) is independently H, unsubstituted C₁-C₈ alkyl, halo or R^(3a)and R^(3b) are taken together to form a carbonyl moiety. In still afurther variation, the compound of the invention is of the Formula (I),where X⁷-X¹⁰ and R¹ are as defined in Formula (I) or as detailed in anyvariation herein, where each R^(2a) and R^(2b) is independently H,unsubstituted C₁-C₈ alkyl, halo or R^(2a) and R^(2b) are taken togetherto form a carbonyl moiety; and each R^(3a) and R^(3b) is independentlyH, unsubstituted C₁-C₈ alkyl, halo or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety. The invention also embracescompounds of the invention according to Formula (I), where X⁷-X¹⁰ and R¹are as defined in Formula (I) or as detailed in any variation herein,where each R^(2a) and R^(2b) is independently H, methyl, halo or R^(2a)and R^(2b) are taken together to form a carbonyl moiety and each R^(3a)and R^(3b) is independently H, methyl, halo or R^(3a) and R^(3b) aretaken together to form a carbonyl moiety. The invention further embracescompounds of the invention according to Formula (I), where X⁷-X¹⁰ and R¹are as defined in Formula (I) or as detailed in any variation herein,where each of R^(2a), R^(2b), R^(3a) and R^(3b) is H. In one variation,a compound of the invention is of the Formula (I) where X⁷-X¹⁰ and R¹are as defined in Formula (I) or as detailed in any variation herein,where at least one of R^(2a), R^(2b), R^(3a) and R^(3b) is a substitutedor unsubstituted C₁-C₈ alkyl, halo, cyano, nitro or is taken togetherwith a geminal R² or R³ to form a carbonyl moiety. In another variation,a compound of the invention is of the Formula (I) where X⁷-X¹⁰ and R¹are as defined in Formula (I) or as detailed in any variation herein,where at least two of R^(2a), R^(2b), R^(3a) and R^(3b) is a substitutedor unsubstituted C₁-C₈ alkyl, halo, cyano, nitro or is taken togetherwith a geminal R² or R³ to form a carbonyl moiety. In yet anothervariation, a compound of the invention is of the Formula (I) whereX⁷-X¹⁰ and R¹ are as defined in Formula (I) or as detailed in anyvariation herein, where at least one of R^(2a), R^(2b), R^(3a) andR^(3b) is fluoro or methyl or is taken together with a geminal R² or R³to form a carbonyl moiety. In still another variation, a compound of theinvention is of the Formula (I) where X⁷-X¹⁰ and R¹ are as defined inFormula (I) or as detailed in any variation herein, where either R^(2a)and R^(2b) or R^(3a) and R^(3b) are each methyl or fluoro (e.g., bothR^(2a) and R^(2b) are methyl or one is fluoro and one is methyl) or aretaken together to form a carbonyl moiety. In one variation, R^(2a) andR^(2b) are taken together to form a carbonyl moiety. In anothervariation, at least one of R^(2a) and R^(2b) is hydroxyl or alkoxy. In aparticular variation, each R^(2a) and R^(2b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro or R^(2a)and R^(2b) are taken together to form a carbonyl. In another variation,when X¹ is N, each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro or R^(2a) and R^(2b) aretaken together to form a carbonyl.

The invention also embraces compounds according to Formula (I), whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in Formula(I) or as detailed in any variation herein, where each R^(10a) andR^(10b) is independently H, halo, an unsubstituted C₁-C₈ alkyl, hydroxylor R^(10a) and R^(10b) are taken, together to form a carbonyl. Alsoembraced are compounds according to Formula (I), where X⁷-X¹⁰, R¹,R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in Formula (I) or asdetailed in any variation herein, where each R^(10a) and R^(10b) isindependently H, halo, an unsubstituted C₁-C₄ alkyl, hydroxyl or R^(10a)and R^(10b) are taken together to form a carbonyl. In another variation,a compound of the invention is of the Formula (I), where X⁷-X¹⁰, R¹,R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in Formula (I) or asdetailed in any variation herein, where each R^(10a) and R^(10b) isindependently H, bromo, methyl, hydroxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl. In yet another variation, a compoundof the invention is of the Formula (I), where X⁷-X¹⁰, R¹, R^(2a),R^(2b), R^(3a) and R^(3b) are as defined in Formula (I) or as detailedin any variation herein, where at least one of R^(10a) and R^(10b) is anunsubstituted C₁-C₈ alkyl, hydroxyl, halo or R^(10a) and R^(10b) aretaken together to form a carbonyl. In still a further variation, acompound of the invention is of the Formula (I), where X⁷-X¹⁰, R¹,R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in Formula (I) or asdetailed in any variation herein, where at least one of R^(10a) andR^(10b) is methyl, bromo, hydroxyl or R^(10a) and R^(10b) are takentogether to form a carbonyl. In another variation, a compound of theinvention is of the Formula (I), X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) andR^(3b) are as defined in Formula (I) or as detailed in any variationherein, where both R^(10a) and R^(10b) are methyl. In another variation,a compound of the invention is of the Formula (I), where X⁷-X¹⁰, R¹,R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in Formula (I) or asdetailed in any variation herein, where R^(10a) and R^(10b) are takentogether to form a carbonyl. In another variation, a compound of theinvention is of the Formula (I), where X⁷-X¹⁰, R¹, R^(2a), R^(2b),R^(3a) and R^(3b) are as defined in Formula (I) or as detailed in anyvariation herein, where R^(10a) is H and R^(10b) is methyl. In anothervariation, a compound of the invention is of the Formula (I), whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in Formula(I) or as detailed in any variation herein, where R^(10a) is H andR^(10b) is bromo. When the carbon of Formula (I) bearing R^(10a) andR^(10b) is optically active, it may be in the S or R configuration andcompositions comprising substantially pure R or S compound or mixturesthereof in any amount are embraced by this invention.

In a particular variation, a compound of the invention is of the Formula(I) where R^(2a), R^(2b), X¹, R^(10a), R^(10b), R^(3a) and R^(3b) aretaken together to form a ring selected from the structures:

where R¹ in the structures above is as defined for Formula (I) or anyparticular variation detailed herein. In another variation, theinvention embraces compounds having R^(2a), R^(2b), X¹, R^(10a),R^(10b), R^(3a) and R^(3b), wherein the substituents R^(2a), R^(2b), X¹,R^(10a), R^(10b), R^(3a) and R^(3b) are taken together to form a moietyof the formula:

In a particular variation, R¹ of any structure or substructure detailedherein is methyl.

Compounds of the formulae (IIa), (IIb), (IIc), (IId), (IIe), (IIf),(IIg) and (IIh) are also embraced by this invention:

where in each of (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) and(IIh), R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b),R^(8a)-R^(8f), m, q and Q are as described for Formula (I) or anyapplicable variation thereof. Where applicable, each of (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIg) and (IIh), R¹, R^(2a), R^(2b), R^(3a),R^(3b), R^(10a), R^(10b), R^(8a)-R^(8f), m, q and Q may also be asdescribed for any formulae or any applicable variation thereof detailedherein, including but not limited to formulae (A)-(G). In one variation,the compound is of the formula (IIa), provided that when X¹ is N, thecompound is other than any of compounds 13x, 30x, 45x, 51x, 53x, 54x,55x, 57x, 58x, 61x, 62x, 65x, 68x, 70x, 72x, 77x, 78x, 79x, 88x, 89x,92x, 93x, 94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x, 126x, 127x, 128x,129x, 130x, 135x, 138x, 140x, 142x, 143x, 144x, 145x, 146x, 156x, 157x,160x, 161x, 163x, 166x, 177x, 179x, 180x, 181x, 182x, 183x, 190x, 192x,195x, 202x, 204x, 205x, 206x, 207x, 208x, 209x, 210x, 211x, 212x, 213x,216x, 217x, 221x, 222x, 223x, 225x, 226x, 227x, 228x, 236x, 237x, 248x,259x, 260x, 261x, 266x, 267x and 268x, or a salt thereof. In anothervariation, the compounds of the invention, and methods of using thecompounds detailed herein, encompass any of the compounds of formula(IIa), including those listed in Table 1, such as 13x, 30x, 45x, 51x,53x-55x, 57x, 58x, 61x, 62x, 65x, 68x, 70x, 72x, 77x-79x, 88x, 89x,92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x, 135x, 138x, 140x,142x-146x, 156x, 157x, 160x, 161x, 163x, 166x, 177x, 179x-183x, 190x,192x, 195x, 202x, 204x-213x, 216x, 217x, 221x-223x, 225x-228x, 236x,237x, 248x, 259x, 260x, 261x, 266x, 267x and 268x, or a salt thereof. Inone variation, the compound is of the formula (IIa) where q is 0, R¹ ismethyl or ethyl and Q is a substituted phenyl.

In one variation, the compound is of the formula (IId) provided thecompound is other than any of compounds 233x, 234x and 235x. In anothervariation, the compounds of the invention, and methods of using thecompounds detailed herein, encompass any of the compounds of formula(IId), including those listed in Table 1, such as compounds 233x, 234xand 235x. In another variation, the compound is of formula (IId)provided that when Q is a substituted piperazinyl, R^(8e) and R^(8f) arenot taken together with the carbon to which they are attached to form acarbonyl. In a further variation, the compound is of formula (IId)provided that when Q is a substituted piperazinyl and R^(8e) and R^(8f)are taken together with the carbon to which they are attached to form acarbonyl, R¹ is other than isopropyl. In a further variation, thecompound is of formula (IId) where R¹ is methyl. In a particularvariation, the compound is of formula (IId) where R¹ is methyl and q is0. In still a further variation, the compound is of formula (IId) whereR¹ is methyl and R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b) andeach of R^(8a)-R^(8f), where present, is hydrogen.

Compounds of the formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe),(IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), (IIIl), (IIIm) arefurther embraced this invention:

where in each of (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg),(IIIh), (IIIi), (IIIj), (IIIk), (IIIl) and (IIIm), R¹, R⁴, R^(2a),R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(8a)-R^(8f), m, q and Q areas described for Formula (I) or any applicable variation thereof. Whereapplicable, in each of (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf),(IIIg), (IIIh), (IIIi), (IIIj), (IIIk), (IIIl) and (IIIm), R¹, R⁴,R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(8a)-R^(8f), m, qand Q may also be as described for any formulae or any applicablevariation thereof detailed herein, including but not limited to formulae(A)-(G).

In one variation, the compound is of the formula (IIIa), provided that(i) when X¹ is N, the compound is other than any of compounds 1x, 2x,3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 11x, 12x, 13x, 15x, 16x, 17x, 18x, 19x,20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x,34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 47x, 49x,50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 65x,68x, 69x, 70x, 72x, 77x, 78x, 79x, 81x, 84x, 85x, 88x, 89x, 90x, 92x,93x, 94x, 95x, 96x, 97x, 98x, 100x, 101x, 102x, 103x, 104x, 105x, 106x,107x, 109x, 110x, 111x, 115x, 116x, 117x, 118x, 119x, 120x, 121x, 122x,123x, 124x, 125x, 126x, 127x, 128x, 129x, 130x, 134x, 135x, 136x, 137x,138x, 139x, 140x, 142x, 143x, 144x, 145x, 146x, 148x, 149x, 150x, 151x,152x, 155x, 156x, 157x, 158x, 159x, 160x, 161x, 162x, 163x, 164x, 165x,166x, 167x, 171x, 174x, 175x, 176x, 177x, 178x, 179x, 180x, 181x, 182x,183x, 184x, 189x, 190x, 191x, 192x, 193x, 194x, 195x, 196x, 198x, 199x,200x, 201x, 202x, 203x, 204x, 205x, 206x, 207x, 208x, 209x, 210x, 211x,212x, 213x, 214x, 216x, 217x, 219x, 220x, 221x, 222x, 223x, 224x, 225x,226x, 227x, 228x, 229x, 231x, 232x, 236x, 237x, 238x, 239x, 243x, 244x,245x, 248x, 249x, 250x, 251x, 252x, 253x, 254x, 255x, 256x, 258x, 259x,260x, 261x, 262x, 263x, 264x, 265x, 266x, 267x, 268x, 269x, 270x, 271x,272x, 273x, 274x, 275x, 276x, 279x, 280x, 281x, 282x, 285x, 286x, 287x,288x, 290x, 291x, 292x, 293x, 294x and 295x, or a salt thereof and (ii)the compound is other than any of compounds 229H, 230, 241, 255, 256,262 and 274 or a salt thereof. In another variation, the compounds ofthe invention, and methods of using the compounds and administering thecompounds detailed herein, encompass any of the compounds of formula(IIIa), including those listed in Table 1, such as 1x-13x, 15x-45x, 47x,49x-62x, 65x, 68x-70x, 72x, 77x-79x, 81x, 84x, 85x, 88x-90x, 92x-98x,100x-107x, 109x-111x, 115x-130x, 134x-140x, 142x-146x, 148x-152x,155x-167x, 171x, 174x-184x, 189x-196x, 198x-214x, 216x, 217x, 219x-229x,231x, 232x, 236x-239x, 243x-245x, 248x-256x, 258x-276x, 279x-282x,285x-288x and 290x-295x, or a salt thereof and compounds 229H, 230, 241,255, 256, 262 and 274, or a salt thereof. In another variation, thecompound is of the formula (IIIa) where R⁴ is other than H, R¹ ismethyl, m is 0 and q is 1 and where Q is a substituted or unsubstitutedaryl, substituted or unsubstituted C₃₋₈ cycloalkyl or a substituted orunsubstituted C₃₋₈ cycloalkenyl. In a particular variation, the compoundis of formula (IIIa) where R⁴ is other than hydrogen; q is 0 and atleast one of (i)-(iii) applies: (i) at least one of R^(8c), R^(8d),R^(8e) and R^(8f) is hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy,carbonylalkoxy, or is taken together with the carbon to which it isattached and a geminal R⁸ to form a cycloalkyl moiety or a carbonylmoiety; (ii) at least one of X⁷-X¹⁰ is N; (iii) m is 0, R^(8c), R^(8d),R^(8e) and R^(8f) are each hydrogen and Q is a substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈cycloalkenyl or substituted or a unsubstituted heterocyclyl, providedthat: (a) when Q is an unsubstituted heteroaryl it is other thanpyridyl; (a) when Q is a substituted heteroaryl, it is other than6-methyl-3-pyridyl; and (c) when Q is an unsubstituted heterocyclyl, itis an unsubstituted heterocyclyl having at least two annularheteroatoms.

In one variation, the compound is of the formula (IIIb), provided thatwhen X¹ is N, the compound is other than any of compounds 13x, 30x, 45x,51x, 53x, 54x, 55x, 57x, 58x, 61x, 62x, 65x, 66x, 67x, 68x, 70x, 72x,77x, 78x, 79x, 88x, 89x, 92x, 93x, 94x, 96x, 97x, 100x, 101x, 104x,105x, 125x, 126x, 127x, 128x, 129x, 130x, 135x, 138x, 140x, 142x, 143x,144x, 145x, 146x, 156x, 157x, 160x, 161x, 163x, 166x, 177x, 179x, 180x,181x, 182x, 183x, 190x, 192x, 195x, 202x, 204x, 205x, 206x, 207x, 208x,209x, 210x, 211x, 212x, 213x, 216x, 217x, 221x, 222x, 223x, 225x, 226x,227x, 228x, 236x, 237x, 248x, 259x, 260x, 261x, 266x, 267x and 268x, ora salt thereof. In another variation, the compounds of the invention,and methods of using the compounds detailed herein, encompass any of thecompounds of formula (IIIb), including those listed in Table 1, such as13x, 30x, 45x, 51x, 53x-55x, 57x, 58x, 61x, 62x, 65x-68x, 70x, 72x,77x-79x, 88x, 89x, 92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x,135x, 138x, 140x, 142x-146x, 156x, 157x, 160x, 161x, 163x, 166x, 177x,179x-183x, 190x, 192x, 195x, 202x, 204x-213x, 216x, 217x, 221x-223x,225x-228x, 236x, 237x, 248x, 259x, 260x, 261x, 266x, 267x and 268x, or asalt thereof. In one variation, the compound is of the formula (IIIb)where R⁴ is other than hydrogen, provided the compound is other than 66xor 67x. In another variation, the compound is of the formula (IIIb)where m is 0, q is 1 and R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl.

In one variation, the compound is of the formula (IIIc), provided thatwhen X¹ is N, the compound is other than any of compounds 13x, 14x, 30x,45x, 51x, 53x, 54x, 55x, 57x, 58x, 61x, 62x, 65x, 68x, 70x, 72x, 77x,78x, 79x, 80x, 82x, 83x, 88x, 89x, 92x, 93x, 94x, 96x, 97x, 100x, 101x,104x, 105x, 125x, 126x, 127x, 128x, 129x, 130x, 132x, 135x, 138x, 140x,141x, 142x, 143x, 144x, 145x, 146x, 156x, 157x, 160x, 161x, 163x, 166x,170x, 177x, 179x, 180x, 181x, 182x, 183x, 187x, 190x, 192x, 195x, 197x,202x, 204x, 205x, 206x, 207x, 208x, 209x, 210x, 211x, 212x, 213x, 216x,217x, 221x, 222x, 223x, 225x, 226x, 227x, 228x, 230x, 236x, 237x, 248x,259x, 260x, 261x, 266x, 267x and 268x, or a salt thereof. In anothervariation, the compounds of the invention, and methods of using thecompounds detailed herein, encompass any of the compounds of formula(IIIc), including those listed in Table 1, such as 13x, 14x, 30x, 45x,51x, 53x-55x, 57x, 58x, 61x, 62x, 65x, 68x, 70x, 72x, 77x-80x, 82x, 83x,88x, 89x, 92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x, 132x,135x, 138x, 140x-146x, 156x, 157x, 160x, 161x, 163x, 166x, 170x, 177x,179x-183x, 187x, 190x, 192x, 195x, 197x, 202x, 204x-213x, 216x, 217x,221x-223x, 225x-228x, 230x, 236x, 237x, 248x, 259x-261x and 266x-268x,or a salt thereof. In one variation, the compound is of the formula(IIIc) where X¹ is N and R⁴ is other than hydrogen, provided thecompound is other than 14x, 80x, 82x, 83x, 132x, 141x, 170x, 187x, 197xor 230x. In one variation, the compound is of the formula (IIIc) whereX¹ is N, R⁴ is other than hydrogen, m is 0 and q is 1, R^(8e) and R^(8f)are both H and Q is other than 6-methyl-3-pyridyl or 4-pyridyl.

In one variation, the compound is of the formula (IIId), provided thatwhen X¹ is N, the compound is other than any of compounds 13x, 30x, 45x,46x, 51x, 53x, 54x, 55x, 57x, 58x, 61x, 62x, 65x, 68x, 70x, 71x, 72x,77x, 78x, 79x, 88x, 89x, 92x, 93x, 94x, 96x, 97x, 100x, 101x, 104x,105x, 125x, 126x, 127x, 128x, 129x, 130x, 135x, 138x, 140x, 142x, 143x,144x, 145x, 146x, 156x, 157x, 160x, 161x, 163x, 166x, 177x, 179x, 180x,181x, 182x, 183x, 185x, 190x, 192x, 195x, 202x, 204x, 205x, 206x, 207x,208x, 209x, 210x, 211x, 212x, 213x, 216x, 217x, 218x, 221x, 222x, 223x,225x, 226x, 227x, 228x, 236x, 237x, 246x, 247x, 248x, 257x, 259x, 260x,261x, 266x, 267x, 268x, 277x, 278x, 283x, 284x and 289x, or a saltthereof. In another variation, the compounds of the invention, andmethods of using the compounds detailed herein, encompass any of thecompounds of formula (IIId), including those listed in Table 1, such as13x, 30x, 45x, 46x, 51x, 53x-55x, 57x, 58x, 61x, 62x, 65x, 68x, 70x-72x,77x-79x, 88x, 89x, 92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x,135x, 138x, 140x, 142x-146x, 156x, 157x, 160x, 161x, 163x, 166x, 177x,179x-183x, 185x, 190x, 192x, 195x, 202x, 204x-213x, 216x-218x,221x-223x, 225x-228x, 236x, 237x, 246x-248x, 257x, 259x-261x, 266x-268x,277x, 278x, 283x, 284x and 289x, or a salt thereof. In a furthervariation, the compound is of the formula (IIId) where R⁴ is other thanhydrogen, provided that the compound is other than any of compounds 46x,71x, 185x, 218x, 246x, 247x, 257x, 277x, 278x, 283x, 284x and 289x. In afurther variation, the compound is of the formula (IIId) where R⁴ isother than hydrogen, m is 0 and q is 1 and Q is other than6-methyl-3-pyridyl and 4-pyridyl. In still a further variation, thecompound is of the formula (IIId) where R⁴ is halo or hydroxyl, m is 0and q is 1.

In one variation, the compound is of the formula (IIIe), provided that(i) when X¹ is N, the compound is other than any of compounds 1x, 2x,3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x,19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x,33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 47x,49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x,65x, 68x, 69x, 70x, 72x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x,88x, 89x, 90x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 100x, 101x, 102x,103x, 104x, 105x, 106x, 107x, 109x, 110x, 111x, 113x, 115x, 116x, 117x,118x, 119x, 120x, 121x, 122x, 123x, 124x, 125x, 126x, 127x, 128x, 129x,130x, 131x, 132x, 134x, 135x, 136x, 137x, 138x, 139x, 140x, 141x, 142x,143x, 144x, 145x, 146x, 148x, 149x, 150x, 151x, 152x, 155x, 156x, 157x,158x, 159x, 160x, 161x, 162x, 163x, 164x, 165x, 166x, 167x, 168x, 169x,170x, 171x, 173x, 174x, 175x, 176x, 177x, 178x, 179x, 180x, 181x, 182x,183x, 184x, 186x, 187x, 189x, 190x, 191x, 192x, 193x, 194x, 195x, 196x,197x, 198x, 199x, 200x, 201x, 202x, 203x, 204x, 205x, 206x, 207x, 208x,209x, 210x, 211x, 212x, 213x, 214x, 216x, 217x, 219x, 220x, 221x, 222x,223x, 224x, 225x, 226x, 227x, 228x, 229x, 230x, 231x, 232x, 236x, 237x,238x, 239x, 243x, 244x, 245x, 248x, 249x, 250x, 251x, 252x, 253x, 254x,255x, 256x, 258x, 259x, 260x, 261x, 262x, 263x, 264x, 265x, 266x, 267x,268x, 269x, 270x, 271x, 272x, 273x, 274x, 275x, 276x, 279x, 280x, 281x,282x, 285x, 286x, 287x, 288x, 290x, 291x, 292x, 293x, 294x and 295x, ora salt thereof and (ii) the compound is other than any of compounds229H, 230, 241, 255, 256, 262 and 274 or a salt thereof. In anothervariation, the compounds of the invention, and methods of using thecompounds and administering the compounds as detailed herein, encompassany of the compounds of formula (IIIe), including those listed in Table1, such as 1x-45x, 47x, 49x-62x, 65x, 68x-70x, 72x, 77x-85x, 88x-90x,92x-98x, 100x-107x, 109x-111x, 113x, 115x-132x, 134x-146x, 148x-152x,155x-171x, 173x-184x, 186x, 187x, 189x-214x, 216x, 217x, 219x-232x,236x-239x, 243x-245x, 248x-256x, 258x-276x, 279x-282x, 285x-288x and290x-295x, or a salt thereof and compounds 229H, 230, 241, 255, 256, 262and 274, or a salt thereof. In another variation, the compound is of theformula (IIIe) where each R⁴ is other than hydrogen, provided that thecompound is other than 113x, 131x, 168x, 169x, 173x or 186x. In anothervariation, the compound is of the formula (IIIe) where each R⁴ is otherthan hydrogen, R^(8e) and R^(8f) are both hydrogen and Q is other than4-pyridyl or 6-methyl-3-pyridyl.

In one variation, the compound is of the formula (IIIf) wherein thecompound is other than any of compounds 233x, 234x and 235x. In anothervariation, the compounds of the invention, and methods of using thecompounds and administering the compounds as detailed herein, encompassany of the compounds of formula (IIIf), including those listed in Table1, such as 233x, 234x or 235x. In another variation, a compound of theinvention is of formula (IIIf) provided that when Q is a substitutedpiperazinyl, R^(8e) and R^(8f) are not taken together with the carbon towhich they are attached to form a carbonyl. In still another variation,a compound of the invention is of formula (IIIf) where R⁴ is other thanhydrogen. In still another variation, a compound of the invention is offormula (IIIf) where R⁴ is methyl or trifluoromethyl. In another suchvariation, a compound of the invention is of formula (IIIf) where R⁴ ismethyl or trifluoromethyl, R¹ is methyl and m is 0 and q is 1.

In one variation, the compound is of the formula (IIIk) wherein thecompound is other than any of compounds 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x,9x, 10x, 11x, 12x, 13x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x,24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x,38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 49x, 50x, 51x, 52x,53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 65x, 68x, 69x, 70x,71x, 72x, 77x, 78x, 79x, 81x, 84x, 85x, 88x, 89x, 90x, 92x, 93x, 94x,95x, 96x, 97x, 98x, 100x, 101x, 102x, 103x, 104x, 105x, 106x, 107x,109x, 110x, 111x, 115x, 116x, 117x, 118x, 119x, 120x, 121x, 122x, 123x,124x, 125x, 126x, 127x, 128x, 129x, 130x, 134x, 135x, 136x, 137x, 138x,139x, 140x, 142x, 143x, 144x, 145x, 146x, 148x, 149x, 150x, 151x, 152x,155x, 156x, 157x, 158x, 159x, 160x, 161x, 162x, 163x, 164x, 165x, 166x,167x, 171x, 172x, 174x, 175x, 176x, 177x, 178x, 179x, 180x, 181x, 182x,183x, 184x, 185x, 189x, 190x, 191x, 192x, 193x, 194x, 195x, 196x, 198x,199x, 200x, 201x, 202x, 203x, 204x, 205x, 206x, 207x, 208x, 209x, 210x,211x, 212x, 213x, 214x, 216x, 217x, 218x, 219x, 220x, 221x, 222x, 223x,224x, 225x, 226x, 227x, 228x, 229x, 231x, 232x, 236x, 237x, 238x, 239x,243x, 244x, 245x, 246x, 247x, 248x, 249x, 250x, 251x, 252x, 253x, 254x,255x, 256x, 257x, 258x, 259x, 260x, 261x, 262x, 263x, 264x, 265x, 266x,267x, 268x, 269x, 270x, 271x, 272x, 273x, 274x, 275x, 276x, 277x, 278x,279x, 280x, 281x, 282x, 283x, 284x, 285x, 286x, 287x, 288x, 289x, 290x,291x, 292x, 293x, 294x and 295x. In another variation, the compounds ofthe invention, and methods of using the compounds and administering thecompounds as detailed herein, encompass any of the compounds of formula(IIIk), including those listed in Table 1, such as compounds 1x-13x,15x-47x, 49x-62x, 65x, 68x-72x, 77x-79x, 81x, 84x, 85x, 88x-90x,92x-98x, 100x-107x, 109x-111x, 115x-130x, 134x-140x, 142x-146x,148x-152x, 155x-167x, 171x, 172x, 174x-185x, 189x-196x, 198x, 199x-214x,216x-229x, 231x, 232x, 236x-239x and 243x-295x. In a further variation,a compound is of the formula (IIIk) where each R⁴ is other thanhydrogen, provided that the compound is other than compound 172x. In afurther variation, a compound is of the formula (IIIk) where each R⁴ isindependently alkyl, hydroxyl or halo, provided that when one R⁴ isalkyl, the other R⁴ is alkyl or hydroxyl. In still a further variation,a compound is of the formula (IIIk) where each R⁴ is independentlyalkyl, hydroxyl or halo and Q is other than 6-methyl-3-pyridyl.

In one variation, the compound is of the formula (IIIl) wherein thecompound is other than any of compounds 13x, 14x, 30x, 45x, 51x, 53x,54x, 55x, 57x, 58x, 61x, 62x, 65x, 66x, 67x, 68x, 70x, 72x, 77x, 78x,79x, 80x, 82x, 83x, 88x, 89x, 92x, 93x, 94x, 96x, 97x, 100x, 101x, 104x,105x, 125x, 126x, 127x, 128x, 129x, 130x, 132x, 135x, 138x, 140x, 141x,142x, 143x, 144x, 145x, 146x, 156x, 157x, 160x, 161x, 163x, 166x, 170x,177x, 179x, 180x, 181x, 182x, 183x, 187x, 190x, 192x, 195x, 197x, 202x,204x, 205x, 206x, 207x, 208x, 209x, 210x, 211x, 212x, 213x, 216x, 217x,221x, 222x, 223x, 225x, 226x, 227x, 228x, 230x, 236x, 237x, 248x, 259x,260x, 261x, 266x, 267x and 268x. In another variation, the compounds ofthe invention, and methods of using the compounds and administering thecompounds as detailed herein, encompass any of the compounds of formula(IIIl), including those listed in Table 1, such as 13x, 14x, 30x, 45x,51x, 53x-55x, 57x, 58x, 61x, 62x, 65x-68x, 70x, 72x, 77x-80x, 82x, 83x,88x, 89x, 92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x, 132x,135x, 138x, 140x-146x, 156x, 157x, 160x, 161x, 163x, 166x, 170x, 177x,179x-183x, 187x, 190x, 192x, 195x, 197x, 202x, 204x-213x, 216x, 217x,221x-223x, 225x-228x, 230x, 236x, 237x, 248x, 259x-261x and 266x-268x.In a further variation, a compound is of the formula (IIIl) where eachR⁴ is other than hydrogen.

In one variation, the compound is of the formula (IIIm) wherein thecompound is other than any of compounds 13x, 30x, 45x, 46x, 48x, 51x,53x, 54x, 55x, 57x, 58x, 61x, 62x, 65x, 66x, 67x, 68x, 70x, 71x, 72x,73x, 74x, 77x, 78x, 79x, 88x, 89x, 91x, 92x, 93x, 94x, 96x, 97x, 100x,101x, 104x, 105x, 125x, 126x, 127x, 128x, 129x, 130x, 135x, 138x, 140x,142x, 143x, 144x, 145x, 146x, 156x, 157x, 160x, 161x, 163x, 166x, 177x,179x, 180x, 181x, 182x, 183x, 185x, 190x, 192x, 195x, 202x, 204x, 205x,206x, 207x, 208x, 209x, 210x, 211x, 212x, 213x, 216x, 217x, 218x, 221x,222x, 223x, 225x, 226x, 227x, 228x, 236x, 237x, 246x, 247x, 248x, 257x,259x, 260x, 261x, 266x, 267x, 268x, 277x, 278x, 283x, 284x and 289x. Inanother variation, the compounds of the invention, and methods of usingthe compounds and administering the compounds as detailed herein,encompass any of the compounds of formula (IIIm), including those listedin Table 1, such as 13x, 30x, 45x, 46x, 48x, 51x, 53x-55x, 57x, 58x,61x, 62x, 65x-68x, 70x-74x, 77x-79x, 88x, 89x, 91x-94x, 96x, 97x, 100x,101x, 104x, 105x, 125x-130x, 135x, 138x, 140x, 142x-146x, 156x, 157x,160x, 161x, 163x, 166x, 177x, 179x-183x, 185x, 190x, 192x, 195x, 202x,204x-213x, 216x-218x, 221x-223x, 225x-228x, 236x, 237x, 246x-248x, 257x,259x-261x, 266x-268x, 277x, 278x, 283x, 284x and 289x. In a furthervariation, a compound is of the formula (IIIm) where each R⁴ is otherthan hydrogen, provided that the compound is other than any of compounds48x, 73x, 74x and 91x. In still a further variation, a compound is ofthe formula (IIIm) where each R⁴ is other than hydrogen, m is 0 and q is1.

Compounds of the formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf),(IVg), (IVh), (IVi), (IVj) and (IVk) are further embraced by thisinvention:

where in each of (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh),(IVi), (IVj) and (IVk), R¹, X⁷, X⁸, X⁹, X¹⁰, X^(8a)-R^(8f), m, q and Qare as described for Formula (I) or any applicable variation thereof.Where applicable, in each of (IVa), (IVb), (IVc), (IVd), (IVe), (IVf),(IVg), (IVh), (IVi), (IVj) and (IVk), R¹, X⁷, X⁸, X⁹, X¹⁰,R^(8a)-R^(8f), m, q and Q may also be as described for any formulae orany applicable variation thereof detailed herein, including but notlimited to formulae (A)-(G).

In one variation, the compound is of the formula (IVa), provided that(i) the compound is other than any of compounds 1x-44x, 47x-50x, 52x,54x-62x, 65x-67x, 71x-74x, 77x, 78x, 80x-85x, 88x-98x, 100x-107x,109x-111x, 113x-146x, 148x-152x, 155x, 157x-179x, 181x-214x, 219x-239xand 243x-295x, or a salt thereof and (ii) the compound is other than anyof compounds 229H, 230, 255, 256, 262 and 274 or a salt thereof. Inanother variation, the compounds of the invention, and methods of usingthe compounds and administering the compounds as detailed herein,encompass any of the compounds of formula (IVa), including those listedin Table 1, such as 1x-44x, 47x-50x, 52x, 54x-62x, 65x-67x, 71x-74x,77x, 78x, 80x-85x, 88x-98x, 100x-107x, 109x-111x, 113x-146x, 148x-152x,155x, 157x-179x, 181x-214x, 219x-239x and 243x-295x, or a salt thereofand compounds 229H, 230, 255, 256, 262 and 274, or a salt thereof.

In one variation, the compound is of the formula (IVb) provided that R¹is NR^(a)R^(b) and either:

(a) each R^(a) and R^(b) is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic,provided that both R^(a) and R^(b) groups are not H, and at least one of(i)-(iii) applies:

-   -   (i) when m and q are 0, at least one of R^(a) and R^(b) is other        than methyl;    -   (ii) when m and q are 0, at least one of X⁷-X¹⁰ is other than        CH;    -   (iii) when m and q are 0, either (a) Q is a other than a        substituted or unsubstituted phenyl or (b) Q is a substituted or        unsubstituted heteroaryl, substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl or        substituted or a unsubstituted heterocyclyl; or

(b) R^(a) and R^(b) are joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring. In one variation offormula (IVb), at least one of m and q is 1, R¹ is NR_(a)R_(b) andeither (a) each R^(a) and R^(b) group is independently selected from thegroup consisting of H, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic, provided that both R^(a) and R^(b) groups are not H; or(b) R^(a) and R^(b) are joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring.

In another variation, the compound is of the (IVj), provided thecompound is other than any of compounds 45x, 46x, 51x, 216x, 217x and218x, or a salt thereof. In another variation, the compounds of theinvention, and methods of using the compounds detailed herein, encompassany of the compounds of formula (IVj), including those listed in Table1, such as 45x, 46x, 51x, 216x, 217x and 218x, or a salt thereof.

The invention also embraces compounds of the formulae (Va)-(Vzv):

where in each of (Va)-(Vzv), R¹, R⁴, R^(8a)-R^(8f), m, q and Q are asdescribed for Formula (I) or any applicable variation thereof. Whereapplicable, each of (Va)-(Vzv), R¹, R⁴, R^(8a)-R^(8f), m, q and Q mayalso be as described for any formulae or any applicable variationthereof detailed herein, including but not limited to formulae (A)-(G).In one variation, the compound is of the formula (Va), provided that thecompound is other than any of compounds 13x, 30x, 54x, 55x, 57x, 58x,61x, 62x, 65x, 72x, 77x, 78x, 88x, 89x, 92x, 93x, 94x, 96x, 97x, 100x,101x, 104x, 105x, 125x, 126x, 127x, 128x, 129x, 130x, 135x, 138x, 140x,142x, 143x, 144x, 145x, 146x, 157x, 160x, 161x, 163x, 166x, 177x, 179x,181x, 182x, 183x, 190x, 192x, 195x, 202x, 204x, 205x, 206x, 207x, 208x,209x, 210x, 211x, 212x, 213x, 221x, 222x, 223x, 225x, 226x, 227x, 228x,236x, 237x, 248x, 259x, 260x, 261x, 266x, 267x and 268x, or a saltthereof. In another variation, the compounds of the invention, andmethods of using the compounds detailed herein, encompass any of thecompounds of formula (Va), including those listed in Table 1, such as13x, 30x, 54x, 55x, 57x, 58x, 61x, 62x, 65x, 72x, 77x, 78x, 88x, 89x,92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x, 135x, 138x, 140x,142x-146x, 157x, 160x, 161x, 163x, 166x, 177x, 179x, 181x-183x, 190x,192x, 195x, 202x, 204x-213x, 221x-223x, 225x-228x, 236x, 237x, 248x,259x, 260x, 261x, 266x, 267x and 268x, or a salt thereof.

In one variation, the compound is of the formula (Vd) provided thecompound is other than any of compounds 233x, 234x and 235x. In anothervariation, the compounds of the invention, and methods of using thecompounds detailed herein, encompass any of the compounds of formula(Vd), including those listed in Table 1, such as 233x, 234x and 235x. Inanother variation, the compound is of formula (Vd) provided that when Qis a substituted piperazinyl, R^(8e) and R^(8f) are not taken togetherwith the carbon to which they are attached to form a carbonyl.

In one variation, the compound is of the formula (Ve), provided that thecompound is other than any of compounds 13x, 30x, 54x, 55x, 57x, 58x,61x, 62x, 65x, 66x, 67x, 72x, 77x, 78x, 88x, 89x, 92x, 93x, 94x, 96x,97x, 100x, 101x, 104x, 105x, 125x, 126x, 127x, 128x, 129x, 130x, 135x,138x, 140x, 142x, 143x, 144x, 145x, 146x, 157x, 160x, 161x, 163x, 166x,177x, 179x, 181x, 182x, 183x, 190x, 192x, 195x, 202x, 204x, 205x, 206x,207x, 208x, 209x, 210x, 211x, 212x, 213x, 221x, 222x, 223x, 225x, 226x,227x, 228x, 236x, 237x, 248x, 259x, 260x, 261x, 266x, 267x and 268x, ora salt thereof. In another variation, the compounds of the invention,and methods of using the compounds detailed herein, encompass any of thecompounds of formula (Ve), including those listed in Table 1, such as13x, 30x, 54x, 55x, 57x, 58x, 61x, 62x, 65x-67x, 72x, 77x, 78x, 88x,89x, 92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x, 135x, 138x,140x, 142x-146x, 157x, 160x, 161x, 163x, 166x, 177x, 179x, 181x-183x,190x, 192x, 195x, 202x, 204x-213x, 221x-223x, 225x-228x, 236x, 237x,248x, 259x, 260x, 261x, 266x, 267x and 268x, or a salt thereof. Inanother variation, the compound is of the formula (Ve) where R⁴ is otherthan hydrogen, provided that the compound is other than any of compounds66x and 67x. In another variation, the compound is of the formula (Ve)where R⁴ is other than hydrogen (e.g., where R⁴ is chloro), m is 0 and qis 1.

In one variation, the compound is of the formula (Vf), provided that thecompound is other than any of compounds 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x,9x, 10x, 11x, 12x, 13x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x,24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x,38x, 39x, 40x, 41x, 42x, 43x, 44x, 47x, 49x, 50x, 52x, 54x, 55x, 56x,57x, 58x, 59x, 60x, 61x, 62x, 65x, 72x, 77x, 78x, 81x, 84x, 85x, 88x,89x, 90x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 100x, 101x, 102x, 103x,104x, 105x, 106x, 107x, 109x, 110x, 111x, 115x, 116x, 117x, 118x, 119x,120x, 121x, 122x, 123x, 124x, 125x, 126x, 127x, 128x, 129x, 130x, 134x,135x, 136x, 137x, 138x, 139x, 140x, 142x, 143x, 144x, 145x, 146x, 148x,149x, 150x, 151x, 152x, 155x, 157x, 158x, 159x, 160x, 161x, 162x, 163x,164x, 165x, 166x, 167x, 171x, 174x, 175x, 176x, 177x, 178x, 179x, 181x,182x, 183x, 184x, 189x, 190x, 191x, 192x, 193x, 194x, 195x, 196x, 198x,199x, 200x, 201x, 202x, 203x, 204x, 205x, 206x, 207x, 208x, 209x, 210x,211x, 212x, 213x, 214x, 219x, 220x, 221x, 222x, 223x, 224x, 225x, 226x,227x, 228x, 229x, 231x, 232x, 236x, 237x, 238x, 239x, 243x, 244x, 245x,248x, 249x, 250x, 251x, 252x, 253x, 254x, 255x, 256x, 258x, 259x, 260x,261x, 262x, 263x, 264x, 265x, 266x, 267x, 268x, 269x, 270x, 271x, 272x,273x, 274x, 275x, 276x, 279x, 280x, 281x, 282x, 285x, 286x, 287x, 288x,290x, 291x, 292x, 293x, 294x and 295x, or a salt thereof. In anothervariation, the compounds of the invention, and methods of using thecompounds and administering the compounds as detailed herein, encompassany of the compounds of formula (Vf), including those listed in Table 1,such as 1x-13x, 15x-44x, 47x, 49x, 50x, 52x, 54x-62x, 65x, 72x, 77x,78x, 81x, 84x, 85x, 88x-90x, 92x-98x, 100x-107x, 109x-111x, 115x-130x,134x-140x, 142x-146x, 148x-152x, 155x, 157x-167x, 171x, 174x-179x,181x-184x, 189x-196x, 198x-214x, 219x-229x, 231x, 232x, 236x-239x,243x-245x, 248x-256x, 258x-276x, 279x-282x, 285x-288x and 290x-295x, ora salt thereof and compounds 229H, 230, 255, 256, 262 and 274 or a saltthereof. In another variation, the compound is of the formula (Vf) whereR⁴ is other than hydrogen, m is 0 and q is 1, and at least one of(i)-(iii) applies: (i) Q is a substituted or unsubstituted aryl, asubstituted or unsubstituted C₃-C₈cycloalkyl or a substituted orunsubstituted C₃-C₈cycloalkenyl; (ii) at least one of R^(8a), R^(8b),R^(8e) and R^(8f) is hydroxyl, C₁-C₈alkyl or is taken together with thecarbon to which it is attached and a geminal R⁸ to form a cycloalkylmoiety or a carbonyl moiety; and (iii) Q is other than piperidyl,azepanyl, 6-methyl-3-pyridyl or 4-pyridyl.

In one variation, the compound is of the formula (Vg), provided that thecompound is other than any of compounds 13x, 14x, 30x, 54x, 55x, 57x,58x, 61x, 62x, 65x, 72x, 77x, 78x, 80x, 82x, 83x, 88x, 89x, 92x, 93x,94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x, 126x, 127x, 128x, 129x,130x, 132x, 135x, 138x, 140x, 141x, 142x, 143x, 144x, 145x, 146x, 157x,160x, 161x, 163x, 166x, 170x, 177x, 179x, 181x, 182x, 183x, 187x, 190x,192x, 195x, 197x, 202x, 204x, 205x, 206x, 207x, 208x, 209x, 210x, 211x,212x, 213x, 221x, 222x, 223x, 225x, 226x, 227x, 228x, 230x, 236x, 237x,248x, 259x, 260x, 261x, 266x, 267x and 268x, or a salt thereof. Inanother variation, the compounds of the invention, and methods of usingthe compounds detailed herein, encompass any of the compounds of formula(Vg), including those listed in Table 1, such as 13x, 14x, 30x, 54x,55x, 57x, 58x, 61x, 62x, 65x, 72x, 77x, 78x, 80x, 82x, 83x, 88x, 89x,92x-94x, 96x, 97x, 100x, 101x, 104x, 105x, 125x-130x, 132x, 135x, 138x,140x-146x, 157x, 160x, 161x, 163x, 166x, 170x, 177x, 179x, 181x-183x,187x, 190x, 192x, 195x, 197x, 202x, 204x-213x, 221x-223x, 225x-228x,230x, 236x, 237x, 248x, 259x-261x and 266x-268x, or a salt thereof. In afurther variation, the compound is of the formula (Vg) where R⁴ is otherthan hydrogen, provided the compound is other than 14x, 80x, 82x, 83x,132x, 141x, 170x, 187x, 197x, 216x, 217x or 230x. In a furthervariation, the compound is of the formula (Vg) where R⁴ is other thanhydrogen, m is 0 and q is 1 and Q is an unsubstituted or substitutedaryl or an unsubstituted or substituted heteroaryl other than 4-pyridylor 6-methyl-3-pyridyl.

In one variation, the compound is of the formula (Vh), provided that thecompound is other than any of compounds 13x, 30x, 54x, 55x, 57x, 58x,61x, 62x, 65x, 71x, 72x, 77x, 78x, 88x, 89x, 92x, 93x, 94x, 96x, 97x,100x, 101x, 104x, 105x, 125x, 126x, 127x, 128x, 129x, 130x, 135x, 138x,140x, 142x, 143x, 144x, 145x, 146x, 157x, 160x, 161x, 163x, 166x, 177x,179x, 181x, 182x, 183x, 185x, 190x, 192x, 195x, 202x, 204x, 205x, 206x,207x, 208x, 209x, 210x, 211x, 212x, 213x, 221x, 222x, 223x, 225x, 226x,227x, 228x, 236x, 237x, 246x, 247x, 248x, 257x, 259x, 260x, 261x, 266x,267x, 268x, 277x, 278x, 283x, 284x and 289x, or a salt thereof. Inanother variation, the compounds of the invention, and methods of usingthe compounds detailed herein, encompass any of the compounds of formula(Vh), including those listed in Table 1, such as 13x, 30x, 54x, 55x,57x, 58x, 61x, 62x, 65x, 71x, 72x, 77x, 78x, 88x, 89x, 92x-94x, 96x,97x, 100x, 101x, 104x, 105x, 125x-130x, 135x, 138x, 140x, 142x-146x,157x, 160x, 161x, 163x, 166x, 177x, 179x, 181x-183x, 185x, 190x, 192x,195x, 202x, 204x-213x, 221x-223x, 225x-228x, 236x, 237x, 246x-248x,257x, 259x-261x, 266x-268x, 277x, 278x, 283x, 284x and 289x, or a saltthereof. In another variation, the compound is of the formula (Vh) whereR⁴ is other than hydrogen, provided the compound is other than any ofcompounds 71x, 185x, 246x, 247x, 257x, 277x, 278x, 283x, 284x and 289x.In still another variation, the compound is of the formula (Vh) where R⁴is other than hydrogen, m is 0 and q is 1 and Q is a substituted orunsubstituted aryl or a substituted heteroaryl. In still anothervariation, the compound is of the formula (Vh) where R⁴ is halo oralkyl, m is 0 and q is 1 and Q is a substituted or unsubstituted phenylor a substituted pyridyl.

In one variation, the compound is of the formula (Vk), provided that R¹is NR_(a)R_(b) and either: (a) each R^(a) and R^(b) is independentlyselected from the group consisting of H, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl and heterocyclicand substituted heterocyclic, provided that both R^(a) and R^(b) groupsare not H; or (b) R^(a) and R^(b) are joined together with the nitrogenatom to form a heterocyclic or substituted heterocyclic ring. In onevariation of (Vk) where R¹ is as defined immediately above and thecompound further has at least one of the following structural features:(i) when m and q are 0, at least one of R^(a) and R^(b) is other thanmethyl, and (ii) when m and q are 0, either (a) Q is a other than asubstituted or unsubstituted phenyl or (b) Q is a substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl,substituted or unsubstituted C₃₋₈ cycloalkenyl or substituted or aunsubstituted heterocyclyl. In one variation of formula (Vk), at leastone of m and q is 1, R¹ is NR_(a)R_(b) and either (a) each R^(a) andR^(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic, provided thatboth R^(a) and R^(b) groups are not H; or (b) R^(a) and R^(b) are joinedtogether with the nitrogen atom to form a heterocyclic or substitutedheterocyclic ring.

In one variation, the compound is of the formula (Vn), provided that (i)the compound is other than any of compounds 1x, 2x, 3x, 4x, 5x, 6x, 7x,8x, 9x, 10x, 11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x,23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x,37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 47x, 49x, 50x, 52x, 54x, 55x,56x, 57x, 58x, 59x, 60x, 61x, 62x, 65x, 72x, 77x, 78x, 80x, 81x, 82x,83x, 84x, 85x, 88x, 89x, 90x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 100x,101x, 102x, 103x, 104x, 105x, 106x, 107x, 109x, 110x, 111x, 113x, 115x,116x, 117x, 118x, 119x, 120x, 121x, 122x, 123x, 124x, 125x, 126x, 127x,128x, 129x, 130x, 131x, 132x, 134x, 135x, 136x, 137x, 138x, 139x, 140x,141x, 142x, 143x, 144x, 145x, 146x, 148x, 149x, 150x, 151x, 152x, 155x,157x, 158x, 159x, 160x, 161x, 162x, 163x, 164x, 165x, 166x, 167x, 168x,169x, 170x, 171x, 173x, 174x, 175x, 176x, 177x, 178x, 179x, 181x, 182x,183x, 184x, 186x, 187x, 189x, 190x, 191x, 192x, 193x, 194x, 195x, 196x,197x, 198x, 199x, 200x, 201x, 202x, 203x, 204x, 205x, 206x, 207x, 208x,209x, 210x, 211x, 212x, 213x, 214x, 219x, 220x, 221x, 222x, 223x, 224x,225x, 226x, 227x, 228x, 229x, 230x, 231x, 232x, 236x, 237x, 238x, 239x,243x, 244x, 245x, 248x, 249x, 250x, 251x, 252x, 253x, 254x, 255x, 256x,258x, 259x, 260x, 261x, 262x, 263x, 264x, 265x, 266x, 267x, 268x, 269x,270x, 271x, 272x, 273x, 274x, 275x, 276x, 279x, 280x, 281x, 282x, 285x,286x, 287x, 288x, 290x, 291x, 292x, 293x, 294x and 295x, or a saltthereof and (ii) the compound is other than any of compounds 229H, 230,255, 256, 262 and 274, or a salt thereof. In another variation, thecompounds of the invention, and methods of using the compounds andadministering the compounds as detailed herein, encompass any of thecompounds of formula (Vn), including those listed in Table 1, such as1x-44x, 47x, 49x, 50x, 52x, 54x-62x, 65x, 72x, 77x, 78x, 80x-85x,88x-90x, 92x-98x, 100x-107x, 109x-111x, 113x, 115x-132x, 134x-146x,148x-152x, 155x, 157x-171x, 173x-179x, 181x-184x, 186x, 187x, 189x-214x,219x-232x, 236x-239x, 243x-245x, 248x-256x, 258x-276x, 279x-282x,285x-288x and 290x-295x or a salt thereof and compounds 229H, 230, 255,256, 262 and 274, or a salt thereof. In still a further variation, thecompound is of formula (Vn) where R⁴ is other than hydrogen, providedthe compound is other than 113x, 131x, 168x, 169x, 173x or 186x. In yeta further variation, the compound is of formula (Vn) where each R⁴ isother than hydrogen and at least one R⁴ is fluoro or hydroxyl. In stillyet a further variation, the compound is of formula (Vn) where each R⁴is independently halo, hydroxyl or alkyl, provided that either (i) atleast one R⁴ is fluoro or hydroxyl or (ii) the R⁴ moieties are not thesame and Q is other than 6-methyl-3-pyridyl.

In one variation, the compound is of the formula (Vo), provided that thecompound is other than any of compounds 233x, 234x and 235x. In anothervariation, the compounds of the invention, and methods of using thecompounds detailed herein, encompass any of the compounds of formula(Vzv), including those listed in Table 1, such as 233x, 234x and 235x.In another variation, the compound is of formula (Vo) provided that whenQ is a substituted piperazinyl, R^(8e) and R^(8f) are not taken togetherwith the carbon to which they are attached to form a carbonyl.

In one variation, the compound is of the formula (Vzv), provided thatthe compound is other than any of compounds 45x, 51x, 216x and 217x or asalt thereof. In another variation, the compounds of the invention, andmethods of using the compounds detailed herein, encompass any of thecompounds of formula (Vzv), including those listed in Table 1, such as45x, 51x, 216x and 217x, or a salt thereof. In still a furthervariation, the compound is of the formula (Vzv) where R⁴ is other thanhydrogen. In still a further variation, the compound is of the formula(Vzv) where R⁴ is alkyl (e.g., methyl).

In one variation, a compound of the invention is of the formula (I) or(Ia) or any variation of the foregoing detailed herein, or is of any oneof the formulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv),where each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) isindependently H, hydroxyl, unsubstituted C₁-C₄ alkyl or is takentogether with the carbon to which it is attached and a geminal R₈ toform a cycloalkyl moiety. Where applicable, such variations applyequally to any formulae detailed herein, such as formula (A)-(G). In onevariation, a compound of the invention is of the formula (I) or (Ia) orany variation of the foregoing detailed herein, or is of any one of theformulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv), where atleast one of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is takentogether with the carbon to which it is attached and a geminal R⁸ toform a carbonyl moiety. In another variation, a compound of theinvention is of the formula (I) or (Ia) or any variation of theforegoing detailed herein, or is of any one of the formulae (IIa)-(IIh),(IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv), where each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl, methylor is taken together with the carbon to which it is attached and ageminal R₈ to form a cyclopropyl moiety. Where applicable, suchvariations apply equally to any formulae detailed herein, such asformula (A)-(G). In yet another variation, a compound of the inventionis of the formula (I) or (Ia) or any variation of the foregoing detailedherein, or is any one of the formulae (IIa)-(IIh), (IIIa)-(IIIm),(Iva)-(IVk) or (Va)-(Vzv), where wherein q is 0 and m is 1. Whereapplicable, such variations apply equally to any formulae detailedherein, such as formula (A)-(G). The invention also embraces a compoundof the invention according to formula (I) or (Ia) or any variation ofthe foregoing detailed herein, or a compound according to any one of theformulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv), where qand m are both 0. Where applicable, such variations apply equally to anyformulae detailed herein, such as formula (A)-(G). The invention furtherembraces a compound according to formula (I) or (Ia) or any variation ofthe foregoing detailed herein, or a compound according to any one of theformulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv), where q,m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken togetherto form a moiety selected from the group consisting of: —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂—C(H)(OH)—, —C(H)(OH)—CH₂—, —CH₂—C(OH)(CH₃)—,—C(OH)(CH₃)—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—CH₂—, —CH₂—C(CH₃)(CH₃)—,—C(CH₂CH₂)—CH₂— and —CH₂—C(CH₂CH₂)—. Where applicable, such variationsapply equally to any formulae detailed herein, such as formula (A)-(G).For example, taking formula A, compounds of the structures listed beloware embraced by the invention:

The invention further embraces a compound according to formula (F) orany variation of the foregoing detailed herein, where q, m, R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form amoiety selected from the group consisting of: —C(H)(C(O)OH)—CH₂—,—C(H)(C(O)OEt)-CH₂—, —C(H)(C(O)OMe)-CH₂—, —CH₂—C(H)(C(O)OH)—,—CH₂—C(H)(C(O)OEt)-, —CH₂—C(H)(C(O)OMe)-, —C(OH)(CF₃)—CH₂— and—CH₂—C(OH)(CF₃)—.

In another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIIa)-(IIIm), (Iva)-(IVk) or(Va)-(Vzv), where each R⁴ is independently H, halo, substituted orunsubstituted C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, substituted orunsubstituted heterocyclyl or a substituted or unsubstituted aryl. Inyet another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIIa)-(IIIm), (Iva)-(IVk) or(Va)-(Vzv), where each R⁴ is independently H or a substituted orunsubstituted C₁-C₈ alkyl. In still another variation, a compound of theinvention is of the formula (I) or (Ia) or any variation of theforegoing detailed herein, or a compound according to any one of theformulae (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv), where each R⁴ is H.The invention also embraces compounds of the formula (I) or (Ia) or anyvariation of the foregoing detailed herein, or a compound according toany one of the formulae (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv), whereeach R⁴ is independently H, halo, unsubstituted C₁-C₄ alkyl, C₁-C₄perhaloalkyl or a substituted or unsubstituted aryl. The inventionfurther embraces compounds of the formula (I) or (Ia) or any variationof the foregoing detailed herein, or a compound according to any one ofthe formulae (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where each R⁴ isindependently H, halo, methyl, perfluoromethyl or cyclopropyl.

The invention also embraces compounds of the formula (I) or (Ia) or anyvariation of the foregoing detailed herein, or a compound according toany one of the formulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or(Va)-(Vzv) where Q is a substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, which may be but is not limited to asubstituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl,imidazolyl, furanyl, pyrrolyl or thiophenyl group. In one variation, acompound of the invention is of the formula (I) or (Ia) or any variationof the foregoing detailed herein, or a compound according to any one ofthe formulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) whereQ is a substituted or unsubstituted phenyl or pyridyl group. In aparticular variation, Q is a phenyl or pyridyl group substituted with atleast one methyl group. In another variation, a compound of theinvention is of the formula (I) or (Ia) or any variation of theforegoing detailed herein, or a compound according to any one of theformulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where Qis a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl,pyrrolyl or thiophenyl group substituted with at least one substitutedor unsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety. In stillanother variation, a compound of the invention is of the formula (I) or(Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIm),(Iva)-(IVk) or (Va)-(Vzv) where Q is a substituted or unsubstituted C₃₋₈cycloalkyl or a substituted or unsubstituted heterocyclyl. In yetanother variation, a compound of the invention is of the formula (I) or(Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIm),(Iva)-(IVk) or (Va)-(Vzv) where Q is a substituted or unsubstitutedpyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinylgroup. In a particular variation, Q is a pyridyl, phenyl, pyrazinyl,piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with atleast one methyl or halo group. In one variation, a compound of theinvention is of the formula (I) or (Ia) or any variation of theforegoing detailed herein, or a compound according to any one of theformulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where Qis an unsubstituted C₃₋₈ cycloalkyl or an unsubstituted heterocyclyl. Inanother variation, a compound of the invention is of the formula (I) or(Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIm),(Iva)-(IVk) or (Va)-(Vzv) where Q is a substituted or unsubstitutedcyclohexyl, morpholinyl, piperizinyl, thiomorpholinyl, cyclopentyl orpyrrolidinyl moiety. In yet another variation, a compound of theinvention is of the formula (I) or (Ia) or any variation of theforegoing detailed herein, or a compound according to any one of theformulae (IIa)-(IIh), (IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where Qis a substituted cyclohexyl, morpholinyl, piperizinyl, thiomorpholinyl,cyclopentyl or pyrrolidinyl moiety substituted with at least onecarbonyl, hydroxymethyl, methyl or hydroxyl group.

In still another variation, a compound of the invention is of theformula (I) or (Ia) or any variation of the foregoing detailed herein,or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where Q is a moiety selectedfrom the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. Inone variation, Q is substituted with no more than one R⁹ group. Inanother variation, Q is substituted with only one R⁹ group. In onevariation, Q is substituted with two R⁹ groups. In a further variation,Q is selected from the aromatic structures detailed where the residuehas the moiety (R⁹)₀ such that Q either contains no R⁹ functionality ora moiety of the formula N—R⁹.

In another variation of any Q moiety detailed herein comprising R⁹, itis understood that variations in which greater than two R⁹ moieties areencompassed by this invention. For example, a phenyl group having fourR⁹ moieties is provided for herein, notwithstanding the depiction insome variations of a phenyl with 0-2 R⁹ moieties. In one variation,where applicable, a Q moiety contains from 3-5 R⁹ moieties.

In another variation, a compound of the invention is of the formula (I),(A), (E) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where Q is a moiety selectedfrom the structures:

In yet another variation, a compound of the invention is of the formula(I) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where Q is a moiety selectedfrom the structures:

and wherein R⁹ is connected to Q ortho or para to the position at whichQ is connected to the carbon bearing R^(8e) and R^(8f). In a particularvariation, Q is a structure of the formula:

and R⁹ is connected to Q para to the position at which Q is connected tothe carbon bearing R^(8e) and R^(8f).

In another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIm),(Iva)-(IVk) or (Va)-(Vzv) where Q is a moiety selected from thestructures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, Q is substituted withno more than one R⁹ group. In another variation, Q is substituted withonly one R⁹ group. In yet another variation, Q is substituted with twoR⁹ groups. In a particular variation, Q is selected from the carbocyclicand heterocyclic structures detailed where the residue has the moiety(R⁹)₀ such that Q either contains no R⁹ functionality or a moiety of theformula N—R⁹.

In any structure or variation detailed herein, in one embodiment, Q is

In any structure or variation detailed herein containing an R⁹ group, inone variation, each R⁹ is independently a substituted or unsubstitutedC₁-C₄ alkyl, halo, trifluoromethyl or hydroxyl. In another variation,each R⁹ is independently methyl, —CH₂OH, isopropyl, halo,trifluoromethyl or hydroxyl.

In another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIm),(Iva)-(IVk) or (Va)-(Vzv) where Q is a moiety selected from thestructures:

In another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIm),(Iva)-(IVk) or (Va)-(Vzv) where Q is a moiety selected from thestructures:

In yet another variation, a compound of the invention is of the formula(I) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIm), (Iva)-(IVk) or (Va)-(Vzv) where Q is a moiety selectedfrom the structures:

In a further variation, a compound of the invention is of the Formula(I) where R¹ is an unsubstituted alkyl, R^(2a), R^(2b), R^(3a), R^(3b),R^(10a), R^(10b) are each H, each X⁷, X⁸, X⁹ and X¹⁰ is independently Nor CH, each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) isindependently H or hydroxyl, and Q is a substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, including but not limitedto a substituted or unsubstituted phenyl or pyridyl group. Where Q is asubstituted phenyl or pyridyl group, in one variation it is substitutedwith at least one methyl group.

In yet a further variation, a compound of the invention is of theFormula (I) where R¹ is a substituted or unsubstituted C₁-C₈ alkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl; each R^(2a) and R^(2b)is independently H, unsubstituted C₁-C₈ alkyl or halo; each R^(3a) andR^(3b) is independently H or halo; each X⁷, X⁸, X⁹ and X¹⁰ is CR⁴, whereR⁴ is as defined in Formula (I) or in a particular variation, R⁴ is H,halo, pyridyl, methyl or trifluoromethyl; R^(10a) and R^(10b) are bothH, and Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, including but not limited to a substituted orunsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl,furanyl, pyrrolyl or thiophenyl group. In a particular variation, Q is apyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolylor thiophenyl group substituted with at least one substituted orunsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety. In onevariation, a compound of the variation detailed herein is providedwherein R¹ is propylate, methyl, ethyl, cyclopropyl, trifluoromethyl,isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal,1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In still a further variation, a compound of the invention is of theFormula (I) where R¹ is a substituted or unsubstituted C₁-C₈ alkyl; eachR^(2a), R^(2b), R^(3a) and R^(3b) is independently H or halo; X¹ is N;each R⁴ is independently H, halo, C₁-C₈ perhaloalkyl, substituted or aunsubstituted C₁-C₈ alkyl; each R^(8a), R^(8b), R^(8c), R^(8e) andR^(8f) is H; and Q is a substituted or unsubstituted cyclohexyl,morpholinyl, piperizinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety. The invention also embraces a compound of the Formula (I) whereR¹ is a methyl; at least one of X⁷, X⁸, X⁹ and X¹⁰ is CR⁴, and each R⁴is independently H, halo, methyl or trifluoromethyl. The inventionembraces compounds where Q in any variation detailed is substituted withat least one carbonyl, hydroxymethyl, methyl or hydroxyl group.

In a particular variation, the compound is of the Formula (I) where R¹is a substituted or unsubstituted C₁-C₈ alkyl; each R^(2a) and R^(2b) isindependently H, a substituted or unsubstituted C₁-C₈ alkyl or R^(2a)and R^(2b) are taken together to form a carbonyl moiety; R^(3a) andR^(3b) are both H; X¹ is N, each R⁴ is independently H, halo orsubstituted or unsubstituted C₁-C₈ alkyl; each R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) is H; each R^(10a) and R^(10b) isindependently H, halo, a substituted or unsubstituted C₁-C₈ alkyl,hydroxyl, alkoxyl or R^(10a) and R^(10b) are taken together to form acarbonyl, provided that at least one of R^(10a) and R^(10b) is otherthan H. In one aspect of this variation, Q may be a substituted orunsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl orthiomorpholinyl group. In another aspect of this variation, Q is apyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinylgroup substituted with at least one methyl or halo group. In yet anotheraspect of this variation, X⁷, X⁸, X⁹ and X¹⁰ are CR⁴ and each R⁴ isindependently H, halo or methyl.

In a particular variation, the invention embraces compounds of theformula (F):

wherein:

R⁴ is halo or C₁-C₄alkyl;

Q is

R⁹ is halo, alkoxy or H provided that when R⁹ is H, R⁴ is other thanfluoro or methyl; and

R^(9A) is perhaloalkyl or alkyl, provided that R^(9A) is other than CH₃,

or a salt or solvate thereof.

In one variation of formula (F), Q is

In one such variation, R⁴ is chloro. In a further variation, R⁴ ischloro and R⁹ is hydrogen. In another variation of formula (F), Q is

In one such variation, R⁴ is halo. In another such variation, R^(9A) isperhaloalkyl. In a still further such variation, R⁴ is halo and R^(9A)is perhaloalkyl (e.g., when R⁴ is chloro and R^(9A) is trifluoromethyl).In a still further such variation, R^(9A) is a C₁-C₄ alkyl (e.g.,propyl, which in one variation is n-propyl and in another isiso-propyl). In yet another variation of formula (F), Q is

Examples of compounds according to the invention are depicted in Table2. The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan.

TABLE 2 Representative Compounds According to the Invention. Com- poundNo. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9H

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38H

 39H

 40H

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59H

 60

 61H

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90H

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109H

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151H

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218H

219H

220H

221

222H

223H

224

225

226

227

228

229H

230

231

232

233

234H

235

236

237

238

239

240

241

242H

243

244

245

246

247

248

249

250

251

252H

253

254H

255

256

257

258H

259H

260H

261H

262

263

264

265

266

267

268

269

270

271

272

273H

274

275

276H

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293H

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394H

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

Additional compounds of the invention include compounds of the formula(G):

where:

R¹ is selected from unsubstituted alkyl and unsubstituted aralkyl orheteroaralkyl;

R¹⁹ is selected from hydrogen, unsubstituted alkyl, unsubstitutedalkoxy, and halo; and

Q is selected from substituted thiazolyl, triazolyl, and oxadiazolyl,

or a pharmaceutically acceptable salt thereof. In one variation, Q is atriazolo-thione.

In some embodiments of formula (G) or any variation herein, such ascompounds of the formula (Ga)-(Gd), R¹⁹ is selected from hydrogen,unsubstituted C₁-C₈ alkyl, unsubstituted C₁-C₈ alkoxy, and halo. In someembodiments, R¹⁹ is selected from hydrogen, unsubstituted C₁-C₄ alkyl,unsubstituted C₁-C₄ alkoxy, and halo. In some embodiments, R¹⁹ isselected from hydrogen, methyl, methoxy, fluoro, and chloro.

In another variation, a compound of the invention is of the formula G orany variation herein, such as compounds of the formula (Ga)-(Gd),wherein the A-ring is selected from the following structures:

In some embodiments the compound is of formula (G) or any variationherein, such as compounds of the formula (Ga)-(Gd), where R¹ is selectedfrom unsubstituted C₁-C₈ alkyl and unsubstituted C₁-C₈ aralkyl orheteroaralkyl. In some embodiments, R¹ is selected from unsubstitutedC₁-C₄ alkyl and unsubstituted C₁-C₄ aralkyl or heteroaralkyl. In someembodiments, R¹ is selected from methyl and benzyl. It is furtherunderstood that any R¹ detailed herein may be combined with anyvariation for R¹⁹. In one variation, both R¹ and R¹⁹ are methyl.

In still a further variation, a compound of the invention is of theformula G or any variation herein, such as compounds of the formula(Ga)-(Gd), wherein the C-ring is selected from the following structures:

In some embodiments, Q is selected from thiazol-2-yl,1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, and1,2,4-oxadiazol-3-yl. In some embodiments, Q is thiazol-2-yl,1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, or1,2,4-oxadiazol-3-yl, substituted with a group selected fromunsubstituted C₁-C₈ alkyl and unsubstituted aryl or heteroaryl. In someembodiments, Q is thiazol-2-yl, 1,2,4-triazol-3-yl,5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, or 1,2,4-oxadiazol-3-yl,substituted with a group selected from unsubstituted C₁-C₄ alkyl andunsubstituted aryl or heteroaryl. In some embodiments, Q isthiazol-2-yl, 1,2,4-triazol-3-yl,5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, or 1,2,4-oxadiazol-3-yl,substituted with a group selected from methyl, phenyl, and pyridin-4-yl.

In another variation, the compound of the invention is of the formula Gwhere rings A and C are as detailed in any variation herein and Q isselected from the following structures:

where R^(13a) is selected from hydrogen and alkyl; R^(14a) is selectedfrom aryl and heteroaryl; R^(13b) is alkyl; R^(13c) is selected fromalkyl, aryl, and heteroaryl; and R^(13d) is selected from aryl andheteroaryl. In another variation, Q is selected from the structuresabove and R^(13a) is selected from hydrogen and methyl; R^(14a) isselected from phenyl and pyridin-4-yl; R^(13b) is methyl; R^(13c) isselected from methyl, phenyl, and pyridin-4-yl; and R^(13d) is selectedfrom phenyl and pyridin-4-yl.

Thus, compounds of Formula (Ga)-(Gd) are embraced by this invention:

In some embodiments, the compound is of Formula Ga, wherein R¹ isselected from methyl and benzyl; R¹⁹ is selected from hydrogen, methyl,methoxy, chloro, and fluoro; R^(13a) is selected from hydrogen andmethyl; and R^(14a) is selected from phenyl and pyridin-4-yl.

In some embodiments, the compound is of Formula Gb, wherein R¹ isselected from methyl and benzyl; R¹⁹ is selected from hydrogen, methyl,methoxy, chloro, and fluoro; and R^(13b) is methyl.

In some embodiments, the compound is of Formula Gc, wherein R¹ isselected from methyl and benzyl; R¹⁹ is selected from hydrogen, methyl,methoxy, chloro, and fluoro; and R^(13c) is selected from methyl,phenyl, and pyridin-4-yl.

In some embodiments, the compound is of Formula Gd, wherein R¹ isselected from methyl and benzyl; R¹⁹ is selected from hydrogen, methyl,methoxy, chloro, and fluoro; and R^(13d) is selected from phenyl andpyridin-4-yl.

Certain examples of compounds according to the invention are depicted inTable 3. The compounds depicted may be present as salts even if saltsare not depicted and it is understood that the invention embraces allsalts, hydrates and solvates of the compounds depicted here, as well asthe non-salt, non-hydrate, non-solvate form of the compound, as is wellunderstood by the skilled artisan. It is thus understood thatpharmaceutically acceptable salts of compounds according the inventionare intended.

TABLE 3 Representative Compounds According to the Invention No.Structure G6-a

G6-b

G6-c

G6-d

G6-e

G6-f

G8-a

G8-b

G8-c

G8-d

G8-e

G8-f

G11-a

G11-b

G11-c

G11-d

Compounds according to the invention as listed in Table 3 are alsoreferred to as follows in the Biological Examples 16B to 19B: G6-a(C4-1); G6-b (C4-5); G6-c (C4-4); G6-d (C4-6); G6-e (C4-3); G6-f (C4-7);G8-a (C1-1); G8-b (C1-6); G8-c (C1-5); G8-d (C1-4); G8-e (C1-8); G8-f(C1-7); G11-a (C2-1); G11-b (C2-5); G11-c (C2-6); and G11-d (C2-4).

Pharmaceutical compositions comprising any of the compounds detailedherein are embraced by this invention. Thus, the invention includespharmaceutical compositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. Provided are pharmaceuticalcompositions comprising a compound disclosed herein or apharmaceutically acceptable salt thereof (e.g., an oxalate salt or a TFAsalt or a hydrochloride salt or dihydrochloride salt) and apharmaceutically acceptable carrier or excipient. Pharmaceuticalcompositions according to the invention may take a form suitable fororal, buccal, parenteral, nasal, topical or rectal administration, or aform suitable for administration by inhalation.

In one variation, compounds of the invention are synthetic compoundsprepared for administration to an individual. In another variation,compositions are provided containing compounds of the invention insubstantially pure form. In another variation, the invention embracespharmaceutical compositions comprising a compound of the invention and apharmaceutically acceptable carrier. In another variation, methods ofadministering a compound of the invention are provided. The purifiedforms, pharmaceutical compositions and methods of administering thecompounds are suitable for any compound or form thereof detailed herein,such as compound 229H, 230, 241, 255, 256, 262 and 274. In particular,where applicable, metabolites of dimebon are in one variation excludedfrom the formulae provided. In another variation, metabolites of dimebonare encompassed by the methods, pharmaceutical compositions, isolatedand purified forms of the compounds of the invention. Such metabolitesare believed to include compounds 229H, 230, 241, 255, 256, 262, 274 andthe compound of Example 93. Compounds substituted with an O-Glu arelikewise excluded in one variation from the compounds of the formulaeprovided.

In one variation, a compound of the invention is according to any of theformulae detailed herein, wherein the compound further is a type 1compound according to the invention. In one variation, a compound of theinvention is according to any of the formulae detailed herein, whereinthe compound further is a type 2 compound according to the invention. Inone variation, a compound of the invention is according to any of theformulae detailed herein, wherein the compound further is a type 3compound according to the invention. In one variation, a compound of theinvention is according to any of the formulae detailed herein, whereinthe compound further is a type 4 compound according to the invention.

Classification of Compounds

The binding properties of compounds disclosed herein to a panel ofaminergic G protein-coupled receptors including adrenergic receptors,dopamine receptors, serotonin receptors, histamine receptors and animidazoline receptor may be determined. Binding properties may beassessed by methods known in the art, such as competitive bindingassays. In one variation, compounds are assessed by the binding assaysdetailed herein. Compounds disclosed herein may also be tested incell-based assays or in in vivo models for further characterization. Inone aspect, compounds disclosed herein are of any formula detailedherein and further display one or more of the following characteristics:inhibition of binding of a ligand to an adrenergic receptor (e.g., α1D,α2A and α2B), inhibition of binding of a ligand to a serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7), inhibition of binding of aligand to a dopamine receptor (e.g., D2L), and inhibition of binding ofa ligand to a histamine receptor (e.g., H1, H2 and H3);agonist/antagonist activity to a serotonin receptor (e.g., 5-HT2A,5-HT6); agonist/antagonist activity to a dopamine receptor (e.g., D2L,D2S); agonist/antagonist activity to a histamine receptor (e.g., H1);activity in a neurite outgrowth assay; efficacy in a preclinical modelof memory dysfunction associated with cholinergic hyperfunction; andefficacy in a preclinical model of schizophrenia. In one variation,inhibition of binding of a ligand to a receptor is measured in theassays described herein. In another variation, inhibition of binding ofa ligand is measured in an assay known in the art. In one variation,binding of a ligand to a receptor is inhibited by at least about 80% asdetermined in a suitable assay known in the art such as the assaysdescribed herein. In one variation, binding of a ligand to a receptor isinhibited by greater than about any one of 80%, 85%, 90%, 95%, 100%, orbetween about 85-95% or between about 90-100% as determined in asuitable assay known in the art such as the assays described herein. Inone variation, binding of a ligand to a receptor is inhibited by atleast about 80%±20% as determined in an assay known in the art. In onevariation, a compound of the invention inhibits binding of a ligand toat least one and as many as eleven receptors detailed herein (e.g. α1D,α2A, α2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2L, H1, H2, H3) and furtherdisplays agonist or antagonist activity to one or more receptorsdetailed herein (e.g., 5-HT2A, 5-HT6, D2L, D2S, H1). In one variation, acompound of the invention inhibits binding of a ligand to at least onereceptor and as many as eleven as detailed herein and further stimulatesneurite outgrowth, e.g. as measured by the assays described herein. Inanother variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein and further stimulates neurite outgrowth. In afurther variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors as detailedherein and further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic hyperfunction. In anothervariation, a compound of the invention inhibits at least one and as manyas eleven receptors as detailed herein, further shows efficacy in apreclinical model of memory dysfunction associated with cholinergichyperfunction and further displays agonist or antagonist activity to oneor more receptors detailed herein. In a further variation, a compound ofthe invention inhibits binding of a ligand to at least one and as manyas eleven receptors as detailed herein, further shows efficacy in apreclinical model of memory dysfunction associated with cholinergichyperfunction and further stimulates neurite outgrowth. In anothervariation, a compound of the invention inhibits at least one and as manyas eleven receptors as detailed herein, further shows efficacy in apreclinical model of memory dysfunction associated with cholinergichyperfunction, further displays agonist or antagonist activity to one ormore receptor detailed herein and further stimulates neurite outgrowth.In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors and furthershows efficacy in a preclinical model of schizophrenia. In anothervariation, a compound of the invention inhibits binding of a ligand toat least one and as many as eleven receptors, further shows efficacy ina preclinical model of schizophrenia and further displays agonist orantagonist activity to one or more receptors detailed herein. In afurther variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth. In a further variation, a compound of the inventioninhibits binding of a ligand to at least one and as many as elevenreceptors, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic hyperfunction and further showsefficacy in a preclinical model of schizophrenia. In another variation,a compound of the invention inhibits binding of a ligand to at least oneand as many as eleven receptors, further shows efficacy in a preclinicalmodel of schizophrenia, further displays agonist or antagonist activityto one or more receptors detailed herein and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergichyperfunction. In another variation, a compound of the inventioninhibits binding of a ligand to at least one and as many as elevenreceptors, further shows efficacy in a preclinical model ofschizophrenia, further stimulates neurite outgrowth and further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic hyperfunction. In a further variation, a compound of theinvention inhibits binding to at least one and as many as elevenreceptors detailed herein, further displays agonist or antagonistactivity to one ore more receptors detailed herein, further stimulatesneurite outgrowth and further shows efficacy in a preclinical model ofschizophrenia. In another variation, a compound of the inventioninhibits binding of a ligand to at least one and as many as elevenreceptors, further shows efficacy in a preclinical model ofschizophrenia, further displays agonist or antagonist activity to one ormore receptors detailed herein, further stimulates neurite outgrowth andfurther shows efficacy in a preclinical model of memory dysfunctionassociated with cholinergic hyperfunction.

In one aspect, compounds of the invention inhibit binding of a ligand toadrenergic receptors α1D, α2A, α2B and inhibit binding of a ligand toserotonin receptor 5-HT6. In another variation, compounds of theinvention inhibit binding of a ligand to adrenergic receptors α1D, α2A,α2B, to serotonin receptor 5-HT6 and to any one or more of the followingreceptors: serotonin receptor 5-HT7, 5-HT2A and 5-HT2C. In anothervariation, compounds of the invention inhibit binding of a ligand toadrenergic receptors α1D, α2A, α2B, to serotonin receptor 5-HT6 and toany one or more of the following receptors: serotonin receptor 5-HT7,5-HT2A and 5-HT2C and further show weak inhibition of binding of aligand to histamine receptor H1 and/or H2. In another variation,compounds of the invention inhibit binding of a ligand to adrenergicreceptors α1D, α2A, α2B, to serotonin receptor 5-HT6 and further showweak inhibition of binding of a ligand to histamine receptor H1 and/orH2. In another variation, compounds of the invention inhibit binding ofa ligand to dopamine receptor D2L. In another variation, compounds ofthe invention inhibit binding of a ligand to dopamine receptor D2L andto serotonin receptor 5-HT2A. In another variation, compounds of theinvention inhibit binding of a ligand to histamine receptor H1. In onevariation binding is inhibited by at least about 80% as measured in asuitable assay such as the assays described herein. In one variation,binding of a ligand to a receptor is inhibited by greater than about anyone of 80%, 85%, 90%, 95%, 100%, or between about 85-95% or about90-100% as determined in a suitable assay known in the art such as theassays described herein. In one variation, compounds of the inventionshow any of the receptor binding aspects detailed herein and furtherdisplay agonist/antagonist activity to one or more of the followingreceptors: serotonin receptor 5-HT2A, serotonin receptor 5-HT6, dopaminereceptor D2L, dopamine receptor D2S and histamine receptor H1. In onevariation, compounds of the invention show any of the receptor bindingaspects detailed herein and further stimulate neurite outgrowth. In onevariation, compounds of the invention show any of the receptor bindingaspects detailed herein and further show efficacy in a preclinical modelof memory dysfunction associated with cholinergic hyperfunction. In onevariation, compounds of the invention show any of the receptor bindingaspects detailed herein and further show efficacy in a preclinical modelof schizophrenia. In one variation, compounds of the invention show anyof the receptor binding aspects detailed herein and further showefficacy in any one or more of agonist/antagonist assays (e.g., toserotonin receptor 5-HT2A, 5-HT6, dopamine receptor D2L, dopaminereceptor D2S and histamine receptor H1), neurite outgrowth, apreclinical model of memory dysfunction associated with cholinergichyperfunction and a preclinical model of schizophrenia.

Compounds of the invention that inhibit binding of a ligand toadrenergic receptors α1D, α2A, α2B and serotonin receptor 5-HT6 by atleast about 80% as determined in a suitable assay such as the assaysdescribed herein can be classified as Type 1 compounds. In onevariation, binding of a ligand to adrenergic receptors α1D, α2A, α2B andserotonin receptor 5-HT6 is inhibited by greater than about any of 80%,85%, 90%, 95%, 100%, between about 85-95% or between about 90-100%, asdetermined in a suitable assay known in the art such as the assaysdescribed herein. Type 1 compounds that also display strong inhibitionof binding of a ligand to the serotonin receptor 5-HT7 are particularlydesired. In one variation, binding of a ligand to serotonin receptor5-HT7 is at least about 80%. In another variation, binding of a ligandto serotonin receptor 5-HT7 is inhibited by greater than about any of80%, 85%, 90%, 95%, 100%, between about 85-95% or between about 90-100%,as determined in a suitable assay known in the art such as the assaysdescribed herein. Weak inhibition of binding of a ligand to thehistamine H1 receptor is permitted as agonists of this receptor havebeen implicated in stimulating memory as well as weight gain. In onevariation, binding to histamine receptor H1 is inhibited by less thanabout 80%. In another variation, binding of a ligand to histaminereceptor H1 is inhibited by less than about any of 75%, 70%, 65%, 60%,55%, or 50% as determined by a suitable assay known in the art such asthe assays described herein. Compounds that inhibit binding of a ligandto the dopamine D2L receptor by at least about 80% as determined in asuitable assay such as the assay described herein can be classified asType 2 compounds. Compounds of the invention that do not inhibit bindingof a ligand to adrenergic receptors α1D, α2A, α2B; serotonin receptor5-HT6 and to the dopamine receptor D2L by at least about 80% asdetermined in a suitable assay such as the assays described herein, butshow activity in neurite outgrowth assays, can be classified as Type 3compounds. Compounds of the invention that do not inhibit binding of aligand to adrenergic receptors α1D, α2A, α2B; serotonin receptor 5-HT6and to the dopamine receptor D2L by at least about 80% as determined ina suitable assay such as the assays described herein, and do not showactivity in neurite outgrowth assays or if the concentration requiredfor neurite outgrowth is greater than 1 μM are referred to as Type 4compounds.

Type 1 Compounds

Type 1 compounds inhibit binding of a ligand to adrenergic receptorsα1D, α2A, α2B and serotonin receptor 5-HT6 by at least about 80% asdetermined by a suitable assay known in the art such as the assaysdescribed herein. In one variation, Type 1 compounds inhibit binding ofProzosin, MK-912 or Rauwolscine to adrenergic receptors α1D, α2A, andα2B, respectively and binding of LSD to serotonin receptor 5-HT6 by atleast about 80% as determined in the assays described herein. In anothervariation, binding is inhibited by greater than about any of 80%, 85%,90%, 95%, 100%, between about 85-95% or between about 90-100%, asdetermined in a suitable assay known in the art such as the assaysdescribed herein. In another variation, inhibition of binding of aligand is at least about 80%±20% as measured by an assay known to aperson skilled in the art. In one variation, Type 1 compounds furtherinhibit binding of a ligand to dopamine receptor D2L by less than about80% as determined in a suitable assay known in the art such as the assaydescribed herein. In certain aspects, Type 1 compounds further show oneor more of the following properties: strong inhibition of binding of aligand to the serotonin 5-HT7 receptor, strong inhibition of binding ofa ligand to the serotonin 5-HT2A receptor, strong inhibition of bindingof a ligand to the serotonin 5-HT2C receptor, weak inhibition of bindingof a ligand to the histamine H1 receptor, weak inhibition of binding ofligands to the histamine H2 receptor, and antagonist activity toserotonin receptor 5-HT2A. In one variation, binding of a ligand toserotonin receptor 5-HT7, 5-HT2A and/or 5-HT2C is inhibited by at leastabout 80% as determined in a suitable assay such as the assays describedherein. In another variation, binding of a ligand to serotonin receptor5-HT7, 5-HT2A and/or 5-HT2C is inhibited by greater than about any of80%, 85%, 90%, 95%, 100%, between about 85-95% or between about 90-100%,as determined in a suitable assay known in the art such as the assaysdescribed herein. In one variation, binding of a ligand to histaminereceptor H1 and/or H2 is inhibited by less than about 80% as determinedby a suitable assay known in the art such as the assays describedherein. In another variation, binding of a ligand to histamine receptorH1 and/or H2 is inhibited by less than about any of 75%, 70%, 65%, 60%,55%, or 50% as determined by a suitable assay known in the art such asthe assays described herein. In one variation, agonist response ofserotonin receptor 5-HT2A is inhibited by a Type 1 compound by at leastabout any one of 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%,150% as determined in a suitable assay such as the assay describedherein.

In some aspects, Type 1 compounds display the above describedneurotransmitter receptor binding profile and further show agonist orantagonist activity one or more of the following receptors: serotoninreceptor 5-HT2A, serotonin receptor 5-HT6, dopamine receptor D2L, anddopamine receptor D2S, histamine receptor H1 as measured in the assaysdescribed herein. In one variation, agonist response of serotoninreceptor 5-HT2A is inhibited by a Type 1 compounds by at least about anyone of 50%, 50%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% asdetermined in a suitable assay such as the assay described herein.

In some aspects, Type 1 compounds display the above describedneurotransmitter receptor binding profile and further stimulate neuriteoutgrowth as determined in a suitable assay such as the assays describedherein. Certain Type 1 compounds showed activity in neurite outgrowthassays using primary neurons in culture (see Example 11B). Data ispresented indicating that a compound of the invention has activitycomparable in magnitude to that of naturally occurring prototypicalneurotrophic proteins such as brain derived neurotrophic factor (BDNF)and nerve growth factor (NGF). Notably, neurite outgrowth plays acritical part of new synaptogenesis, which is beneficial for thetreatment of neuronal disorders. In one variation, neurite outgrowth isobserved with a potency of about 1 μM as measured in a suitable assayknown in the art such as the assays described herein. In anothervariation, neurite outgrowth is observed with a potency of about 500 nM.In a further variation, neurite outgrowth is observed with a potency ofabout 50 nM. In another variation, neurite outgrowth is observed with apotency of about 5 nM.

In certain aspects, Type 1 compounds display the above describedneurotransmitter receptor binding profile and further show pro-cognitiveeffects in a preclinical model of memory dysfunction. Type 1 compoundshave been shown to be effective in a preclinical model of memorydysfunction associated with cholinergic hypofunction (see Example 12B).As H1 antagonism may contribute to sedation, weight gain and reducedcognition, low affinity (less than about 80% inhibition of binding ofPyrilamine at 1 uM in the assay described herein) for this receptor maybe associated with pro-cognitive effects and a more desirable sideeffect profile. Furthermore, Type 1 compounds with increased potency asa 5-HT6 antagonist may have cognition-enhancing effects as serotoninacting through this receptor may impair memory.

In another aspect, Type 1 compounds display the above describedneurotransmitter receptor binding profile and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia. In another variation, Type 1 compounds display the abovedescribed neurotransmitter receptor binding profile and do not possessanti-psychotic effects as measured in a preclinical model ofschizophrenia.

In one variation, Type 1 compounds display the above describedneurotransmitter binding profile, display agonist or antagonist activityto at least one receptor detailed herein and further stimulate neuriteoutgrowth. In a further variation, Type 1 compounds display the abovedescribed neurotransmitter binding profile, further display agonist orantagonist activity to at least one receptor detailed herein and furthershow pro-cognitive effects in a preclinical model of memory dysfunction.In a further variation, Type 1 compounds display the above describedneurotransmitter binding profile, further display agonist or antagonistactivity to at least one receptor detailed herein, and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia. In a further variation, Type 1 compounds display theabove described neurotransmitter binding profile, further stimulateneurite outgrowth and further show pro-cognitive effects in apreclinical model of memory dysfunction. In a further variation, Type 1compounds display the above described neurotransmitter binding profile,further stimulate neurite outgrowth and further possess anti-psychoticeffects as measured in a preclinical model of schizophrenia. In afurther variation, Type 1 compounds display the above describedneurotransmitter binding profile, further show pro-cognitive effects ina preclinical model of memory dysfunction and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia. In one variation, Type 1 compounds display the abovedescribed neurotransmitter binding profile, further display agonist orantagonist activity to at least one receptor detailed herein, furtherstimulate neurite outgrowth and further show pro-cognitive effects in apreclinical model of memory dysfunction. In one variation, Type 1compounds display the above described neurotransmitter binding profile,further display agonist or antagonist activity to at least one receptordetailed herein, further stimulate neurite outgrowth and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia. In one variation, Type 1 compounds display the abovedescribed neurotransmitter binding profile, further stimulate neuriteoutgrowth, further show pro-cognitive effects in a preclinical model ofmemory dysfunction and further possess anti-psychotic effects asmeasured in a preclinical model of schizophrenia. In one variation, Type1 compounds display the above described neurotransmitter bindingprofile, display agonist or antagonist activity to at least one receptordetailed herein, further stimulate neurite outgrowth, further showpro-cognitive effects in a preclinical model of memory dysfunction andfurther possess anti-psychotic effects as measured in a preclinicalmodel of schizophrenia.

Accordingly, in one aspect, Type 1 compounds are particularly useful forthe treatment of cognition and memory-related disorders, including butnot limited to: Alzheimer's Disease, Huntington's Disease, Parkinson'sDisease, amyotrophic, lateral sclerosis (ALS), autism, mild cognitiveimpairment (MCI), cognitive impairment associated with schizophrenia orother psychotic disorders, stroke, traumatic brain injury (TBI) andage-associated memory impairment (AAMI) and pathogen-induced cognitivedysfunction, e.g. HIV associated cognitive dysfunction, Lyme diseaseassociated cognitive dysfunction. In another aspect, Type 1 compoundsare particularly useful for the treatment of neurotransmitter-mediateddisorders including, but not limited to spinal cord injury, diabeticneuropathy, and diseases involving geroprotective activity such asage-associated hair loss (alopecia), age-associated weight loss andage-associated vision disturbances (cataracts).

Type one compounds of the invention include compound 37, 26, 28, 29, 32,43, 47, 45, 83, 162, 89, 250, 68, 357, 55, 60, 404, 371, 452, 56, 333,334, 360, 372, 443, 444, 456, 476, 487, and 225.

Type 2 Compounds

Type 2 compounds inhibit binding of a ligand to the dopamine receptorD2L by at least about 80% as determined in a suitable assay known in theart such as the assay described herein. In one variation, Type 2compounds inhibit binding of Spiperone to the dopamine receptor D2L byat least about 80% as determined in the assay described herein. Inanother variation, binding is inhibited by greater than about any of80%, 85%, 90%, 95%, 100%, between about 85-95% or between about 90-100%,as determined in a suitable assay known in the art such as the assaydescribed herein. In another variation, inhibition of binding of aligand is at least about 80%±20% as measured by an assay known to aperson skilled in the art. In certain aspects, Type 2 compounds furthershow strong inhibition of binding of a ligand to serotonin receptor5-HT2A as determined in the assay described herein. In one variation,biding to serotonin receptor 5-HT2A is inhibited by at least about 80%as determined in a suitable assay know in the art such as the assaydescribed herein. In another variation, binding is inhibited by greaterthan about any of 80%, 85%, 90%, 95%, 100%, between about 85-95% orbetween about 90-100%, as determined in a suitable assay known in theart such as the assay described herein. In some aspects, Type 2compounds inhibit binding of a ligand to adrenergic receptors α1D, α2A,α2B, serotonin receptor 5-HT6 and dopamine receptor D2L by at leastabout 80% as determined in a suitable assay known in the art such as theassays described herein. In one variation, Type 2 compounds inhibitbinding of a ligand to adrenergic receptors α1D, α2A, α2B, serotoninreceptor 5-HT6 and dopamine receptor D2L by at least about 80% asdetermined in a suitable assay known in the art such as the assaysdescribed herein. In another variation, Type 2 compounds inhibit bindingof a ligand to adrenergic receptors α1D, α2A, α2B, serotonin receptor5-HT6 and dopamine receptor D2L by greater than about any of 80%, 85%,90%, 95%, 100%, between about 85-95%, or between about 90-100%, asdetermined in a suitable assay known in the art such as the assaysdescribed herein. As H1 antagonism may contribute to sedation, weightgain and reduced cognition, low affinity (less than about 80% inhibitionof binding of Pyrilamine at 1 uM in the assay described herein) for thisreceptor may be associated with pro-cognitive effects and a moredesirable side effect profile.

In some aspects, Type 2 compounds display the above describedneurotransmitter receptor binding profile and further show agonist orantagonist activity one or more of the following receptors: serotoninreceptor 5-HT2A, serotonin receptor 5-HT6, dopamine receptor D2L,dopamine receptor D2S and histamine receptor H1 as measured in asuitable assay such as the assays described herein. In one variation,Type 2 compounds inhibit agonist response to serotonin receptor 5-HT2Aby at least about any one of 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%,130%, 140%, 150% as determined in a suitable assay such as the assaydescribed herein. In one variation, Type 2 compounds inhibit agonistresponse to dopamine receptor D2L by at least about any one of 50%, 60%,70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% as determined in asuitable assay such as the assay described herein. In one variation,Type 2 compounds inhibit agonist response to dopamine receptor D2S by atleast about any one of 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%,140%, 150% as determined in a suitable assay such as the assay describedherein.

In some aspects, Type 2 compounds display the above describedneurotransmitter receptor binding profile and further show antipsychoticeffects. It is recognized that Type 2 compounds have binding profilessimilar to compounds with antipsychotic activity and several Type 2compounds have been shown to be effective in a preclinical model ofschizophrenia (see Example 13B). In addition, Type 2 compounds mightpossess the cognitive enhancing properties of dimebon and thus add tothe beneficial pharmacology profile of these antipsychotic molecules. Inone variation, Type 2 compounds display the above describedneurotransmitter receptor binding profile and further show pro-cognitiveeffects in a preclinical model of memory dysfunction. In anothervariation, Type 2 compounds display the above described neurotransmitterreceptor binding profile and do not show pro-cognitive effects in apreclinical model of memory dysfunction.

In some aspects, Type 2 compounds display the above describedneurotransmitter receptor binding profile and further stimulate neuriteoutgrowth as determined in a suitable assay such as the assays describedherein. Certain Type 2 compounds showed activity in neurite outgrowthassays using primary neurons in culture (see Example 11B). In onevariation, neurite outgrowth is observed with a potency of about 1 μM.In another variation, neurite outgrowth is observed with a potency ofabout 500 nM. In a further variation, neurite outgrowth is observed witha potency of about 50 nM. In another variation, neurite outgrowth isobserved with a potency of about 5 nM.

In one variation, Type 2 compounds display the above describedneurotransmitter binding profile, display agonist or antagonist activityto at least one receptor detailed herein and further stimulate neuriteoutgrowth. In a further variation, Type 2 compounds display the abovedescribed neurotransmitter binding profile, further display agonist orantagonist activity to at least one receptor detailed herein and furthershow pro-cognitive effects in a preclinical model of memory dysfunction.In a further variation, Type 2 compounds display the above describedneurotransmitter binding profile, further display agonist or antagonistactivity to at least one receptor detailed herein, and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia. In a further variation, Type 2 compounds display theabove described neurotransmitter binding profile, further stimulateneurite outgrowth and further show pro-cognitive effects in apreclinical model of memory dysfunction. In a further variation, Type 2compounds display the above described neurotransmitter binding profile,further stimulate neurite outgrowth and further possess anti-psychoticeffects as measured in a preclinical model of schizophrenia. In afurther variation, Type 2 compounds display the above describedneurotransmitter binding profile, further show pro-cognitive effects ina preclinical model of memory dysfunction and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia. In one variation, Type 2 compounds display the abovedescribed neurotransmitter binding profile, further display agonist orantagonist activity to at least one receptor detailed herein, furtherstimulate neurite outgrowth and further show pro-cognitive effects in apreclinical model of memory dysfunction. In one variation, Type 2compounds display the above described neurotransmitter binding profile,further display agonist or antagonist activity to at least one receptordetailed herein, further stimulate neurite outgrowth and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia. In one variation, Type 2 compounds display the abovedescribed neurotransmitter binding profile, further stimulate neuriteoutgrowth, further show pro-cognitive effects in a preclinical model ofmemory dysfunction and further possess anti-psychotic effects asmeasured in a preclinical model of schizophrenia. In one variation, Type2 compounds display the above described neurotransmitter bindingprofile, display agonist or antagonist activity to at least one receptordetailed herein, further stimulate neurite outgrowth, further showpro-cognitive effects in a preclinical model of memory dysfunction andfurther possess anti-psychotic effects as measured in a preclinicalmodel of schizophrenia.

Accordingly, in one aspect, Type 2 compounds are particularly useful forthe treatment of psychotic indications such as schizophrenia, bipolardisorder, psychosis, depression and anxiety.

Type 2 compounds include compound 25, 20, 34, 32, 33, 36, 247, 253, 336,349, 337, and 455.

Type 3 Compounds

Type 3 compounds do not inhibit binding of a ligand to adrenergicreceptors α1D, α2A, α2B; serotonin receptor 5-HT6 and to the dopaminereceptor D2L by at least about 80% as determined in a suitable assaysuch as the assays described herein, but are active in neurite outgrowthassays, e.g., in the assays described herein. Certain Type 3 compoundsshowed activity in neurite outgrowth assays using primary neurons inculture (see Example 11B). In one variation, neurite outgrowth isobserved with a potency of less than or equal to about 1 μM. In anothervariation, neurite outgrowth is observed with a potency of about 500 nM.In a further variation, neurite outgrowth is observed with a potency ofabout 50 nM. In another variation, neurite outgrowth is observed with apotency of about 5 nM.

In some aspects, Type 3 compounds display the above describedneurotransmitter receptor binding profile and further show pro-cognitiveeffects. As H1 antagonism may contribute to sedation, weight gain andreduced cognition, low affinity (less than about 80% inhibition ofbinding of Pyrilamine at 1 uM in the assay described herein) for thisreceptor may be associated with pro-cognitive effects and a moredesirable side effect profile. In a further variation, Type 3 compoundsdisplay the above described neurotransmitter receptor binding profileand further possess anti-psychotic effects. In another variation, Type 3compounds display the above described neurotransmitter receptor bindingprofile and do not possess anti-psychotic effects.

In one variation, Type 3 compounds display the above describedneurotransmitter binding profile, further stimulate neurite outgrowthand further show pro-cognitive effects in a preclinical model of memorydysfunction. In another variation, Type 3 compounds display the abovedescribed neurotransmitter binding profile, further stimulate neuriteoutgrowth and further possess anti-psychotic effects as measured in apreclinical model of schizophrenia. In a further variation, Type 3compounds display the above described neurotransmitter binding profile,further stimulate neurite outgrowth, further show pro-cognitive effectsin a preclinical model of memory dysfunction and further possessanti-psychotic effects as measured in a preclinical model ofschizophrenia.

Accordingly, in one aspect, Type 3 compounds are particularly useful forthe treatment of neuronal disorders such as Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson'sdisease, canine cognitive dysfunction syndrome (CCDS), Lewy bodydisease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahrdisease, an acute or chronic disorder involving cerebral circulation,such as ischemic or hemorrhagic stroke or other cerebral hemorrhagicinsult, age-associated memory impairment (AAMI), mild cognitiveimpairment (MCI), injury-related mild cognitive impairment (MCI),post-concussion syndrome, post-traumatic stress disorder and adjuvantchemotherapy, traumatic brain injury, (TBI), neuronal death mediatedocular disorder, macular degeneration, age-related macular degeneration,autism, including autism spectrum disorder, Asperger syndrome, and Rettsyndrome, an avulsion injury, a spinal cord injury, myasthenia gravis,Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy,fibromyalgia, neuropathy associated with spinal cord injury,schizophrenia, bipolar disorder, psychosis, anxiety and depression. Inanother aspect, Type 3 compounds are particularly suitable for thetreatment of neurotransmitter-mediated disorders including, but notlimited to spinal cord injury, diabetic neuropathy, allergic diseasesand diseases involving geroprotective activity such as age-associatedhair loss (alopecia), age-associated weight loss and age-associatedvision disturbances (cataracts).

Type 3 compounds include compound 395.

Type 4 Compounds

Type 4 compounds do not inhibit binding of a ligand to adrenergicreceptors α1D, α2A, α2B; serotonin receptor 5-HT6 and to the dopaminereceptor D2L by at least about 80% as determined in a suitable assaysuch as the assays described herein and are effective in a neuriteoutgrowth assay only with a potency of greater than about 1 μM. In onevariation, Type 4 compounds are not active in a neurite outgrowth assay.

In one variation, Type 4 compounds show pro-cognitive effects in apreclinical model of memory dysfunction. In another variation, Type 4compounds do not show pro-cognitive effects in a preclinical model ofmemory dysfunction. In a further variation, Type 4 compounds possessanti-psychotic effects in a preclinical model of schizophrenia. Inanother variation, Type 4 compounds do not possess anti-psychoticeffects in a preclinical model of schizophrenia. In a further variation,Type 4 compounds show pro-cognitive effects in a preclinical model ofmemory dysfunction and further possess anti-psychotic effects in apreclinical model of schizophrenia.

Accordingly, in one aspect, Type 4 compounds are particularly useful forthe treatment of neuronal disorders such as Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson'sdisease, canine cognitive dysfunction syndrome (CCDS), Lewy bodydisease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahrdisease, an acute or chronic disorder involving cerebral circulation,such as ischemic or hemorrhagic stroke or other cerebral hemorrhagicinsult, age-associated memory impairment (AAMI), mild cognitiveimpairment (MCI), injury-related mild cognitive impairment (MCI),post-concussion syndrome, post-traumatic stress disorder and adjuvantchemotherapy, traumatic brain injury, (TBI), neuronal death mediatedocular disorder, macular degeneration, age-related macular degeneration,autism, including autism spectrum disorder, Asperger syndrome, and Rettsyndrome, an avulsion injury, a spinal cord injury, myasthenia gravis,Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy,fibromyalgia, neuropathy associated with spinal cord injury,schizophrenia, bipolar disorder, psychosis, anxiety and depression. Inanother aspect, Type 4 compounds are particularly suitable for thetreatment of neurotransmitter-mediated disorders including, but notlimited to spinal cord injury, diabetic neuropathy, allergic diseasesand diseases involving geroprotective activity such as age-associatedhair loss (alopecia), age-associated weight loss and age-associatedvision disturbances (cataracts).

Overview of the Methods

The compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of cognitive disorders, psychoticdisorders, neurotransmitter-mediated disorders and/or neuronal disordersin individuals, such as humans. In one aspect, the compounds describedherein may be used to treat, prevent, delay the onset and/or delay thedevelopment of a cognitive disorder. In another aspect, the compoundsdescribed herein may be used to treat, prevent, delay the onset and/ordelay the development of a psychotic disorder. In yet another aspect,the compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of a neurotransmitter-mediateddisorders disorder. In one embodiment, the neurotransmitter-mediateddisorder includes spinal cord injury, diabetic neuropathy, allergicdiseases (including food allergies) and diseases involvinggeroprotective activity such as age-associated hair loss (alopecia),age-associated weight loss and age-associated vision disturbances(cataracts). In another variation, the neurotransmitter-mediateddisorder includes spinal cord injury, diabetic neuropathy, fibromyalgiaand allergic diseases (including food allergies). In still anotherembodiment, the neurotransmitter-mediated disorder includes Alzheimer'sdisease, Parkinson's Disease, autism, Guillain-Barre syndrome, mildcognitive impairment, multiple sclerosis, stroke and traumatic braininjury. In yet another embodiment, the neurotransmitter-mediateddisorder includes schizophrenia, anxiety, bipolar disorders, psychosisand depression. In another aspect, the compounds described herein may beused to treat, prevent, delay the onset and/or delay the development ofa neuronal disorder. In one aspect, the compounds described herein mayalso be used to treat, prevent, delay the onset and/or delay thedevelopment of cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders for whichthe modulation of an aminergic G protein-coupled receptor is believed tobe or is beneficial.

The invention also provides methods of improving cognitive functionsand/or reducing psychotic effects comprising administering to anindividual in need thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to improve cognitivefunctions and/or reduce psychotic effects.

The invention also provides methods of stimulating neurite outgrowthand/or promoting neurogenesis and/or enhancing neurotrophic effects inan individual comprising administering to an individual in need thereofan amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof effective to stimulate neurite outgrowth and/orto promote neurogenesis and/or to enhance neurotrophic effects.

The invention further encompasses methods of modulating an aminergic Gprotein-coupled receptor comprising administering to an individual inneed thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor.

It is to be understood that methods described herein also encompassmethods of administering compositions comprising the compounds of theinvention.

Methods for Treating, Preventing, Delaying the Onset, and/or Delayingthe Development Cognitive Disorders, Psychotic Disorders,Neurotransmitter-Mediated Disorders and/or Neuronal Disorders

In one aspect, the invention provides methods for treating, preventing,delaying the onset, and/or delaying the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial, the methodcomprising administering to an individual in need thereof a compound ofthe invention. In some variations, modulation of adrenergic receptorα1D, α2A, α2B, serotonin receptor 5-HT2A, 5-HT6, 5HT7, histaminereceptor H1 and/or H2 is expected to be or is beneficial for thecognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, modulation ofadrenergic receptor α1D, α2A, α2B and a serotonin receptor 5-HT6receptor is expected to be or is beneficial for the cognitive disorders,psychotic disorders, neurotransmitter-mediated disorders and/or neuronaldisorders. In some variations, modulation of adrenergic receptor α1D,α2A, α2B, and a serotonin receptor 5-HT6 receptor and modulation of oneor more of the following receptors serotonin 5-HT7, 5-HT2A, 5-HT2C andhistamine H1 and H2 is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In some variations, modulation of dopaminereceptor D2L is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In certain variations, modulation of adopamine D2L receptor and serotonin receptor 5-HT2A is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders aretreated, prevented and/or their onset or development is delayed byadministering a Type 1 compound. In some variations, the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders are treated, prevented and/or their onset ordevelopment is delayed by administering a Type 2 compound. In somevariations, the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders aretreated, prevented and/or their onset or development is delayed byadministering a Type 3 compound. In some variations, the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders are treated, prevented and/or their onset ordevelopment is delayed by administering a Type 4 compound.

Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects

The invention provides methods for improving cognitive functions byadministering a compound of the invention to an individual in needthereof. In some variations, modulation of one or more of adrenergicreceptor α1D, α2A, α2B, serotonin receptor 5-HT2A, 5-HT6, 5HT7,histamine receptor H1 and/or H2 is desirable or expected to be desirableto improve cognitive functions. In some variations modulation of α1D,α2A, α2B adrenergic receptors and a serotonin 5-HT6 receptor isdesirable or expected to be desirable to improve cognitive functions. Insome variations, modulation of α1D, α2A, α2B adrenergic receptors andserotonin receptor 5-HT6 and modulation of one or more of the followingreceptors: serotonin receptor 5-HT7, 5-HT2A, 5-HT2C and histaminereceptor H1 and H2, is desirable or expected to be desirable to improvecognitive functions. In another aspect, the invention encompassesmethods to reduce psychotic effects by administering a compound of theinvention to an individual in need thereof. In some embodiments,modulation of a dopamine D2L receptor is expected to be or is desirableto reduce psychotic effects. In some embodiments, modulation of adopamine D2L receptor and a serotonin 5-HT2A receptor is expected to beor is desirable to reduce psychotic effects. In some variations, a Type1 compound is administered to an individual in need thereof. In somevariations, a Type 2 compound is administered to an individual in needthereof. In some variations, Type 3 compounds are administered to anindividual in need thereof. In some variations, Type 4 compounds areadministered to an individual in need thereof.

Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/orEnhance Neurotrophic Effects

In a further aspect, the invention provides methods of stimulatingneurite outgrowth and/or enhancing neurogenesis and/or enhancingneurotrophic effects comprising administering a compound of theinvention or pharmaceutically acceptable salt thereof under conditionssufficient to stimulate neurite outgrowth and/or to enhance neurogenesisand/or enhance neurotrophic effects to an individual in need thereof. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 1 μM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 500 nMas measured in a suitable assay such as the assays described herein. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 50 nM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 5 nM asmeasured in a suitable assay such as the assays described herein. Insome variations, the compound of the invention is a Type 1 compound. Insome variations, the compound of the invention is a Type 2 compound. Insome variations, the compound of the invention is a Type 3 compound. Insome variations, the compound of the invention is a Type 4 compound.

Methods to Modulate an Aminergic G Protein-Coupled Receptor

The invention further contemplates methods for modulating the activityof an aminergic G-protein-coupled receptor comprising administering acompound of the invention or pharmaceutically acceptable salt thereofunder conditions sufficient to modulate the activity of an aminergic Gprotein-coupled receptor. In some variations, the compound of theinvention is a Type 1 compound. In some variations, the compound of theinvention is a Type 2 compound. In some variations, the compound of theinvention is a Type 3 compound. In some variations, the compound of theinvention is a Type 4 compound. In some variations, the aminergic Gprotein-coupled receptor is a α1D, α2A, α2B adrenergic receptor and aserotonin 5-HT6 receptor. In some variations, the aminergic Gprotein-coupled receptor is a α1D, α2A, α2B adrenergic receptor and aserotonin 5-HT6 and 5-HT7 receptor. In some variations, the aminergic Gprotein-coupled receptor is a α1D, α2A, α2B adrenergic receptor, aserotonin 5-HT6 and one or more of the following receptors: serotonin5-HT-7,5-HT2A and 5-HT2C and histamine H1 and H2 receptor. In somevariations, the aminergic G protein-coupled receptor is a dopamine D2Lreceptor. In some variations, the aminergic G protein-coupled receptoris a dopamine D2L receptor and a serotonin 5-HT2A receptor. In somevariations, the aminergic G protein-coupled receptor is a histamine H1receptor.

Additional Methods

In one aspect, compounds 162x, 177x, 150x, 174x, 155x, 184x, 171x, 133x,131x, 132x, 170x, 151x, 141x, 169x, 172x, 173x, or 168x are used totreat, prevent, delay the onset and/or delay the development ofcognitive disorders. In one variation, compounds 162x, 177x, 150x, 174x,155x, 184x, 171x, 133x, 131x, 132x, 170x, 151x, 141x, 169x, 172x, 173x,or 168x are used to treat, prevent, delay the onset and/or delay thedevelopment of psychotic disorders. In a further variation, compounds162x, 177x, 150x, 174x, 155x, 184x, 171x, 133x, 131x, 132x, 170x, 151x,141x, 169x, 172x, 173x, or 168x are used to treat, prevent, delay theonset and/or delay the development of neuronal indications. In a furthervariation, compounds 162x, 177x, 150x, 174x, 155x, 184x, 171x, 133x,131x, 132x, 170x, 151x, 141x, 169x, 172x, 173x, or 168x are used totreat, prevent, delay the onset and/or delay the development of spinalcord injury, diabetic neuropathy, and diseases involving geroprotectiveactivity.

In another aspect, compounds 152x, 137x, 139x, 159x or 165x are used totreat, prevent, delay the onset and/or delay the development ofcognitive disorders. In one variation, compounds 152x, 137x, 139x, 159xand 165x are used to treat, prevent, delay the onset and/or delay thedevelopment of psychotic disorders. In a further variation, compounds152x, 137x, 139x, 159x and 165x are used to treat, prevent, delay theonset and/or delay the development of neuronal indications. In a furthervariation, compounds 152x, 137x, 139x, 159x and 165x are used to treat,prevent, delay the onset and/or delay the development of spinal cordinjury, diabetic neuropathy, and/or diseases involving geroprotectiveactivity.

In a further aspect, compound 167 is used to treat, prevent, delay theonset and/or delay the development of cognitive disorders. In onevariation, compound 167 is used to treat, prevent, delay the onsetand/or delay the development of psychotic disorders. In a furthervariation, compound 167 is used to treat, prevent, delay the onsetand/or delay the development of neuronal indications. In a furthervariation, compound 167 is used to treat, prevent, delay the onsetand/or delay the development of neurotransmitter-mediated diseasesexcept diseases mediated via serotonin.

In a further aspect, compounds 188x, 190x or 199x are used to treat,prevent, delay the onset and/or delay the development of cognitivedisorders. In one variation, compounds 188x, 190x and 199x are used totreat, prevent, delay the onset and/or delay the development ofpsychotic disorders. In a further variation, compounds 188x, 190x and199x are used to treat, prevent, delay the onset and/or delay thedevelopment of neurotransmitter-mediated disorders. In anothervariation, compounds 188x, 190x and 199x are used to treat, prevent,delay the onset and/or delay the development of neuronal indications.

In a further aspect, compound 134x is used to treat, prevent, delay theonset and/or delay the development of spinal cord injury, diabeticneuropathy, neuropathy associated with nerve injury, avulsion injury,myasthenia gravis, Guillain-Barre syndrome, multiple sclerosis, andfibromyalgia.

In another aspect, compound 178x is used to treat, prevent, delay theonset and/or delay the development of spinal cord injury, allergicdiseases and diseases involving geroprotective activity. In onevariation, compound 178x is used to treat, prevent, delay the onsetand/or delay the development of avulsion injury, myasthenia gravis,Guillain-Barre syndrome, multiple sclerosis, and fibromyalgia.

In another aspect, compound 140x is used to treat, prevent, delay theonset and/or delay the development of spinal cord injury, diseasesinvolving geroprotective activity, avulsion injury, myasthenia gravis,Guillain-Barre syndrome, multiple sclerosis, and/or fibromyalgia.

In a further aspect, compound 56x is used to treat, prevent, delay theonset and/or delay the development of spinal cord injury, allergicdiseases, avulsion injury, myasthenia gravis, Guillain-Barre syndrome,multiple sclerosis, and fibromyalgia.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to formula (I) or a variation thereofunless otherwise indicated.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

The following abbreviations are used herein: thin layer chromatography(TLC); Hour (h); Ethanol (EtOH); dimethylsulfoxide (DMSO);N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); tetrahydrofuran(THF); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane(DCM); Retention factor (Rf).

While certain solvents, temperatures and reaction times are shown hereinby way of example, other variations are possible and one skilled in theart would optimize the conditions, for example, based on the choice ofstarting materials.

A method of synthesizing an intermediate used in the synthesis ofcompounds of the invention is shown as General Method 1.

Compound A (1 equiv) and compound B (0.76-1.4 equiv) are mixed in asuitable solvent such as EtOH and heated at 80° C. for 16 h (overnight)after which the solvent is removed in vacuo. The remaining residue isbasified, e.g., with saturated aq. NaHCO₃. The aqueous layer isextracted with dichloromethane and the combined organic layers are driedover Na₂SO₄, concentrated in vacuo, and purified, e.g., by silica gelchromatography (230-400 mesh) using a suitable solvent gradient such aseither a methanol-dichloromethane gradient or an ethyl acetate-hexanegradient.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 2.

Compound C (1 equiv), compound D (2-20 equiv) and NaH (1-20 equiv) areheated either in DMSO at 100-120° C. for 72 h or in DMF at 120-200° C.for 5-24 h. Contents are cooled to 25° C., quenched by careful additionof methanol or water, and evaporated to dryness under vacuo. Theresulting crude product is purified, e.g., by silica gel chromatography(100-200 mesh or 230-400 mesh) by using methanol-dichloromethanegradient and/or by reverse-phase chromatography (C-18, 500 mm×50 mm,Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

A method of synthesizing compounds of the invention is shown in GeneralMethod 3.

Compound C (1 equiv), compound F (2-20), sodium (0.2-0.8 equiv), andCuSO₄ (catalytic) are heated in EtOH at 120° C. for 16 h. The contentsare evaporated to dryness under vacuo. Water is added and the contentsare extracted with ethyl acetate, dried over anhydrous sodium sulfate,and concentrated. The resulting crude product is purified byreverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05%TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in30 min, injection vol: 5 mL) and/or silica gel (230-400 mesh)chromatography eluting with methanol-dichloromethane gradient.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 4.

Compound C (1 equiv), compound H (2-10 equiv) and NaH (3 equiv) areheated in DMF 120° C. for 16 h. Contents are cooled to 25° C., quenchedby careful addition of methanol or water and evaporated to dryness undervacuo. The resulting crude product is purified by silica gelchromatography (100-200 mesh or 230-400 mesh) by usingmethanol-dichloromethane gradient and/or by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

A method of synthesizing certain compounds of the invention is shown inGeneral Method 5.

Compound C (1 equiv) and compound J (1.8-2.5 equiv) in diisopropylamineare heated at 80° C. for 12 h. The contents are basified with 1N NaOHand extracted with ethyl acetate. The organic layer was dried oversodium sulfate and concentrated. The resulting crude product is purifiedby silica gel chromatography (230-400 mesh) usingmethanol-dichloromethane gradient followed by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

A method of synthesizing certain compounds of the invention is shown inGeneral Method 6.

Compound C (1 equiv), compound L (4-7.5 equiv) and NaH (3 equiv) areheated in DMF at 120° C. for 16 h. The contents are quenched by methanoland evaporated to dryness. The resulting crude product is purified bysilica gel chromatography (230-400 mesh) using methanol-dichloromethanegradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm,Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

A method of synthesizing certain compounds of the invention is shown inGeneral Method 7.

Compound C (1 equiv), compound N (2.05 equiv) and K₃PO₄ (1.9 equiv) inDMF:H₂O (2:1) are purged with nitrogen for 30 minutes after whichPdCl₂(PPh₃)₂ (25 mg, 0.04 mmol) is added and the contents are heated at100° C. for 4 h. The contents are concentrated in vacuo and the crudeproduct is purified by silica gel chromatography (230-400 mesh) toobtain compound O. The compound O (1 equiv), 2-methyl-5-vinylpyridine(12-15 equiv) and NaH (3-4 equiv) are heated in DMSO at 100° C. for 48h. The contents are quenched by methanol and evaporated to dryness. Theresulting crude product is purified by silica gel chromatography(230-400 mesh) using methanol-dichloromethane gradient to obtaincompound Q.

A method of synthesizing compounds of the invention is shown in GeneralMethod 8.

Compound A (1 equiv), triethyl amine (1 equiv) and compound R (1 equiv)are dissolved in EtOH and heated at 80° C. for 2 h after which compoundB (1 to 1.5 equiv) is added and the contents are heated at 80° C. foradditional 16 h. Solvent is removed in vacuo. The remaining residue isdiluted with EtOAc and washed with saturated aq. NaHCO₃. The aqueouslayer is extracted twice with ethyl acetate and combined organic layeris dried over Na₂SO₄, and concentrated. The resulting crude product waspurified by silica gel chromatography (100-200 mesh or 230-400 mesh)using methanol-dichloromethane gradient, by neutral alumina using ethylacetate-hexane gradient, and/or by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

A method of synthesizing compounds of the invention is shown in GeneralMethod 9.

In general, a suitably substituted hydrazine U can be reacted with anappropriately substituted alkyl halide V to generate a substitutedhydrazine W, where the internal nitrogen on the hydrazine issubstituted, as shown above. The reaction of intermediate W with anappropriately substituted cyclohexanone X should provide structures ofthe type generally described by structure Y.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 10.

In general, a suitably substituted hydrazine U can be reacted with anappropriately substituted alkyl halide V to generate a substitutedhydrazine W, where the internal nitrogen on the hydrazine issubstituted, as shown above. The reaction of intermediate W with anappropriately substituted 4-dialkylamino cyclohexanone Z, wherein R^(a)and R^(b) are as defined hereinabove for “substituted amino”, shouldprovide structures of the type generally described by structure AA. Byanalogy, using appropriately substituted 3-dialkylamino cyclohexanonesshould provide compounds of the type described by general structures ABand AC.

Reference: Journal of Medicinal Chemistry, 1977, Volume 20, Number 4,page 487-492.

A method of synthesizing an intermediate used in the synthesis ofcertain compounds of the invention is shown as General Method 11.

See: Helvetica Chimica Acta, 2001, Volume 84, page 2347-2354.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 12.

Reaction of the N-(2-oxoethyl)amide shown above with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide)should provide entry into compounds of Formula Ga.

See: Helvetica Chimica Acta, 2001, Volume 84, page 2347-2354.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 13.

Reaction of the acid chloride shown above with thiosemicarbazides(containing R^(13b)) followed by heating in the presence of aqueoussodium bicarbonate should allow for entry into compounds of Formula Gb.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 14.

Reaction of the acyl hydrazine shown above with different alkylisothiocyanates (containing R^(13b)), followed by heating in thepresence of aqueous sodium bicarbonate should allow for entry intocompounds of Formula Gb.

See: Journal of Medicinal Chemistry, 1994, Volume 37, pp 125-132.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 15.

Reaction of the acyl hydrazine shown above with acid chlorides, eitheralkyl, aryl or heteroaryl, should allow for entry into compounds ofFormula Gc.

See: Synlett, 2005, No. 17, pp 2595-2598.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 16.

Reaction of the hydroxyamidine shown above with different aromatic andheteroaromatic acids, should allow for entry into compounds of FormulaGd.

See: Tetrahedron Letters, 2006, 47, pp 2965-2967.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 17.

Reaction of about a 1:1 mixture of starting materials 701 and 702 in analcohol solvent, for example, ethanol, containing an acid, for example,5% hydrogen chloride in ethanol, at reflux should allow entry intocompounds of Formula Ga. Hal is halo, for example, chloro or bromo, andR¹, R¹⁹, R^(13a), and R^(14a), are defined as hereinabove.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 18.

Reaction of about a 1:1 mixture of starting materials 801 and 802 in analcohol solvent, for example, methanol or ethanol, at reflux shouldprovide intermediate compounds such as 803. Subsequent heating of 803 atabout 180-270° C. should allow entry into compounds of Formula Gc. Alkis alkyl, for example, methyl or ethyl, and R¹, R¹⁹, and R^(13c) aredefined as hereinabove.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 19.

Reaction of about a 1:1:1 mixture of starting materials 901, 902, forexample, R^(13d)COOEt, and 903, for example, sodium ethoxide, in analcohol solvent, for example, ethanol, at reflux should providecompounds of Formula Gd. Alk is alkyl, for example, methyl or ethyl, andR¹, R¹⁹, and R^(13d) are defined as hereinabove.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 20.

Reaction of about a 1:1-1.3 mixture of starting materials 901 and 1001in a basic organic solvent, for example, pyridine, at reflux shouldprovide compounds of Formula Gd. R¹, R¹⁹, and R^(13d) are defined ashereinabove.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 21.

Compounds 59H, 61H, 90H and 109H are synthesized according to GeneralMethod 21.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 22.

Compounds 222H, 223H, 234H and 242H are synthesized according to GeneralMethod 22.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 23.

Compounds 9H, 38H, 39H and 40H are synthesized according to GeneralMethod 23.

A method of synthesizing certain compounds of the invention is shown inGeneral Method 24.

Compounds 151H, 218H, 219H and 220H are synthesized according to GeneralMethod 24.

The methods detailed above may be adapted as known by those of skill inthe art. Particular examples of each General Method are provided in theExamples below.

The following Examples are provided to illustrate but not limit theinvention.

All references disclosed herein are incorporated by reference in theirentireties.

EXAMPLES Example 1 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole

Preparation of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indolewas carried out according to General Method 1. Specifically,4-methylphenylhydrazine hydrochloride (5 g, 31.5 mmol) andN-methyl-4-piperidone hydrochloride (3.6 g, 24 mmol) were mixed in EtOH(150 mL) and heated at 80° C. for 16 h (overnight) after which thesolvent was removed in vacuo. The remaining residue was basified withsaturated aq. NaHCO₃. The aqueous layer was extracted withdichloromethane and the combined organic layers were dried over Na₂SO₄,concentrated in vacuo, and purified by silica gel chromatography(230-400 mesh) using a methanol-dichloromethane gradient to obtain the4.1 g (65% yield) of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole. TLC (Mercksilica gel 60F-254) Rf=0.1 (10% MeOH in DCM).

Example 2 Preparation of8-bromo-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole

Preparation of8-bromo-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole was carriedout according to General Method 1 using 4-bromophenylhydrazinehydrochloride (10 g, 44.7 mmol) and N-methyl-4-piperidone hydrochloride(9.3 g, 62.6 mmol) in EtOH (400 mL) to obtain 2.5 g (21% yield) of8-bromo-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole afterpurification.

Example 3 Preparation of2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole

Preparation of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole wascarried out according to General Method 1 using phenylhydrazinehydrochloride (5 g, 34.6 mmol) and N-methyl-4-piperidone hydrochloride(7.2 g, 48.4 mmol) in EtOH (200 mL) to obtain 3.75 g (58.3% yield) of2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole after purification.

Example 4 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole

Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole was carriedout according to General Method 1 using 4-chlorophenylhydrazinehydrochloride (10 g, 55.8 mmol) and N-methyl-4-piperidone hydrochloride(11.68 g, 78.19 mmol) in EtOH (400 mL) to obtain 3.1 g (25% yield) of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole afterpurification.

Example 5 Preparation of2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

Preparation of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole wascarried out according to General Method 1, using phenylhydrazinehydrochloride (3.4 g, 23.5 mmol) and N-ethyl-4-piperidone hydrochloride(5.3 g, 32.9 mmol) in EtOH (150 mL) to obtain 1.4 g (30% yield) of2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole after purification.

Example 6 Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole

Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole was carriedout according to General Method 1, using 4-methylphenylhydrazinehydrochloride (5 g, 31.5 mmol) and N-ethyl-4-piperidone hydrochloride (4g, 24.5 mmol) in EtOH (150 mL) to obtain 4.8 g (71% yield) of2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole afterpurification.

Example 7 Preparation of ethyl8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Preparation of ethyl8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate was carriedout according to General Method 1 using 4-bromophenylhydrazinehydrochloride (447 mg, 2 mmol) and N-carbethoxy-4-piperidone (342 mg, 2mmol) in EtOH (10 mL) to obtain 423 mg (65% yield) of ethyl8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate afterpurification.

Example 8 Preparation of ethyl8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Preparation of ethyl8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate wascarried out according to General Method 1 using 4-methylphenylhydrazinehydrochloride (317 mg, 2 mmol) and N-carbethoxy-4-piperidone (342 mg, 2mmol) in EtOH (10 mL) to obtain 340 mg (65% yield) of8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate afterpurification.

Example 9 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole.(Compound 25)

Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indolewas carried out according to General Method 2.2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1)(200 mg, 1 mmol), 4-methylstyrene (239 mg, 2.3 mmol) and NaH (120 mg,60% dispersion in oil, 3 mmol) were heated in DMSO (4 ml) at 120° C.overnight (16 h) after which methanol was added and the contents wereconcentrated to dryness. The resulting crude product was purified byreverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05%TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in30 min, injection vol: 5 mL) and/or silica gel (230-400 mesh)chromatography eluting with methanol-dichloromethane gradient to obtain20 mg (6.2% yield) of2,3,4,5-tetrahydro-2,8-dimethyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt.

Example 10 Preparation of ethyl8-bromo-3,4-dihydro-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.(Compound 18)

Preparation of ethyl8-bromo-3,4-dihydro-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylatewas carried out according to General Method 2. The title compound wasprepared from ethyl8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (SeeExample 7) (25 mg, 0.056 mmol), 2-methyl-5-vinyl pyridine (0.12 mL) andNaH (10 mg, 60% dispersion in oil, 0.25 mmol) in DMSO (0.3 ml) to obtain4.5 mg of ethyl8-bromo-3,4-dihydro-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylateafter purification.

Example 11 Preparation of ethyl3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.(Compound 24)

The title compound was prepared according to General Method 2. Ethyl3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylatewas prepared from ethyl8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (SeeExample 8) (257 mg, 1 mmol), styrene (239 mg, 2.3 mmol) and NaH (120 mg,60% dispersion in oil, 3 mmol) in DMSO (5 ml) at 120° C. for overnight(16 h) to obtain 15 mg of ethyl3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylateafter purification.

Example 12 Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.(Compound 37)

The title compound was prepared according to General Method 2.2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indolewas prepared from2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example6) (100 mg, 0.46 mmol), styrene (1 mL, 8.41 mmol) and NaH (200 mg, 60%dispersion in oil, 8.30 mmol) in DMF (3 ml) at 200° C. for 5 h to obtain15 mg (4.7% yield) of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.

Example 13 Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole.(Compound 26)

The title compound was prepared according to General Method 2.2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indolewas prepared from2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example6) (100 mg, 0.4 mmol), 4-methylstyrene (1 mL, 7.6 mmol) and NaH (100 mg,60% dispersion in oil, 2.5 mmol) in DMF (2 ml) at 180° C. for 24 h toobtain 13 mg of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indoleafter purification.

Example 14 Preparation of2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole.(Compound 1)

The title compound was prepared according to General Method 2.2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(See Example 3) (200 mg, 1.07 mmol), 4-methylstyrene (1.41 mL, 10.7mmol) and NaH (250 mg, 60% dispersion in oil, 6.25 mmol) in DMF (6 ml)at 200° C. for 16 h to obtain 7 mg of2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indoleafter purification.

Example 15 Preparation of2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.(Compound 2)

The title compound was prepared according to General Method 2.2,3,4,5-Tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole wasprepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200mg, 1.07), styrene (1.23 mL mmol, 10.65) and NaH (250 mg, 6.25 mmol) inDMF (6 ml) at 200° C. for 16 h to obtain 15 mg of2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole afterpurification.

Example 16 Preparation of2-ethyl-2,3,4,5-tetrahydro-5-phenethyl-1H-pyrido[4,3-b]indole. (Compound4)

The title compound was prepared according to General Method 2.2-Ethyl-2,3,4,5-tetrahydro-5-phenethyl-1H-pyrido[4,3-b]indole wasprepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (SeeExample 5) (100 mg, 0.5 mmol), styrene (1 mL, 8.64 mmol) and NaH (200mg, 5 mmol) in DMF (4 ml) at 150° C. for 16 h to obtain 15 mg of2-ethyl-2,3,4,5-tetrahydro-5-phenethyl-1H-pyrido[4,3-b]indole afterpurification.

Example 17 Preparation of2-ethyl-2,3,4,5-tetrahydro-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole.(Compound 3)

The title compound was prepared according to General Method 2.2-Ethyl-2,3,4,5-tetrahydro-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indolewas prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (SeeExample 5) (100 mg, 0.5 mmol), 4-methylstyrene (1 mL, 6.72 mmol) and NaH(200 mg, 5 mmol) in DMF (4 ml) at 150° C. for 16 h to obtain 16 mg of2-ethyl-2,3,4,5-tetrahydro-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indoleafter purification.

Example 18 Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 31)

Preparation of the title compound was carried out according to GeneralMethod 2.2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indolewas prepared from2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example6) (214 mg, 1 mmol), 2-methyl-5-vinylpyridine (1 mL, 2.3 mmol) and NaH(120 mg, 3 mmol) in DMSO (4 ml) at 120° C. for 48 h to obtain 10 mg of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indoleafter purification.

Example 19 Preparation of5-(4-chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole.(Compound 32)

The title compound was prepared according to General Method 2.5-(4-Chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(See Example 1) (500 mg, 2.5 mmol), 4-chlorostyrene (3.18 mL, 25 mmol)and NaH (300 mg, 7.5 mmol) in DMF (10 ml) at 180° C. for overnight (16h) to obtain 15 mg of5-(4-chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indoleafter purification.

Example 20 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 21)

The title compound was prepared according to General Method 3.2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1)(400 mg, 2 mmol), 2-vinylpyridine (500 mg, 5 mmol), sodium (30 mg, 1.3 gatom), and CuSO₄ (20 mg, catalytic) were heated in EtOH (8 mL) at 150°C. overnight (16 h). The contents were evaporated to dryness undervacuo. Water was added and the contents were extracted with ethylacetate, dried over anhydrous sodium sulfate, and concentrated. Theresulting crude product was purified by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL)to obtain 15 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt.

Example 21 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 22)

The title compound was prepared according to General Method 3.2,3,4,5-Tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(See Example 1) (100 mg, 0.5 mmol), 4-vinylpyridine (120 mg, 1.14 mmol)and sodium (5 mg, 0.21 g atom) in ethanol (1 mL) at 120° C. for 16 h toobtain 4.5 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indoleafter purification on silica gel (230-400 mesh) chromatography elutingwith methanol-dichloromethane gradient.

Example 22 Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 23)

The title compound was prepared according to General Method 3.2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indolewas prepared from2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example6) (214 mg, 1 mmol), 2-vinylpyridine (0.25 ml, 2.3 mmol), sodium (15 mg,0.65 g atom) and CuSO₄ (10 mg, catalytic) in ethanol (2 mL) at 120° C.for 48 h to obtain 15 mg of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt after purification on reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 23 Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 27)

The title compound was prepared according to General Method 3.2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indolewas prepared from2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example6) (214 mg, 1 mmol), 4-vinylpyridine (0.25 ml, 2.3 mmol), sodium (15 mg,0.65 g atom) and CuSO₄ (10 mg, catalytic) in ethanol (2 mL) at 120° C.for overnight (16 h) to obtain 6 mg of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt after purification on reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 24 Preparation of2-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1H-pyrido[4,3-b]indole.(Compound 5)

The title compound was prepared according to General Method 3.2-Ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1H-pyrido[4,3-b]indole wasprepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (SeeExample 5) (200 mg, 1 mmol), 4-vinylpyridine (0.26 mg, 2.5 mmol), andsodium (15 mg, 0.65 g atom) in ethanol (2 mL) at 150° C. overnight (16h) to obtain 10 mg of2-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1H-pyrido[4,3-b]indole as atrifluoroacetate salt after purification on reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 25 Preparation of2-ethyl-2,3,4,5-tetrahydro-5-(2-pyridyl)-1H-pyrido[4,3-b]indole.(Compound 6)

The title compound was prepared according to General Method 3.2-Ethyl-2,3,4,5-tetrahydro-5-(2-pyridyl)-1H-pyrido[4,3-b]indole wasprepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (SeeExample 5) (200 mg, 1 mmol), 2-vinylpyridine (0.26 mg, 2.5 mmol), sodium(15 mg, 0.65 g atom) and CuSO₄ (10 mg, catalytic) in ethanol (2 mL) at150° C. for 16 h to obtain 8 mg of2-ethyl-2,3,4,5-tetrahydro-5-(2-pyridyl)-1H-pyrido[4,3-b]indole as atrifluoroacetate salt after purification on reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 26 Preparation of2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 26)

The title compound was prepared according to General Method 3.2,3,4,5-Tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(See Example 3) (200 mg, 1 mmol), 2-vinylpyridine (0.26 mg, 2.5 mmol),sodium (5 mg, 0.21 g atom) and CuSO₄ (5 mg, catalytic) in ethanol (4 mL)at 120° C. for 16 h (overnight) to obtain 60 mg of2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt after purification on reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 27 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 30)

The title compound was prepared according to General Method 3.8-Chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indolewas prepared from8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example4) (220 mg, 1 mmol), 2-vinylpyridine (1 ml, 18 mmol), sodium (20 mg,0.87 g atom) and CuSO₄ (20 mg, catalytic) in ethanol (5 mL) at 150° C.for 16 h (overnight) to obtain 38 mg of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indoleafter purification on reverse-phase chromatography (C-18, 500 mm×50 mm,Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) followed bypurification on silica gel (230-400 mesh) chromatography eluting withmethanol-dichloromethane gradient.

Compound 54 is prepared according to the process described in Example 27using the appropriately substituted reagents:8-chloro-2,3,4,5-tetrahydro-2-ethyl-1H-pyrido[4,3-b]indole,2-vinylpyridine, sodium and CuSO₄ in ethanol.

Example 28 Preparation of2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 10)

The title compound was prepared according to General Method 3.2,3,4,5-Tetrahydro-2-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(See Example 3) (200 mg, 1.07 mmol), 4-vinylpyridine (0.26 mL, 2.41mmol), sodium (5 mg, 0.21 g atom) and CuSO₄ (5 mg, catalytic) in ethanol(4 mL) at 120° C. for 16 h (overnight) to obtain 60 mg of2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indoleas trifluoroacetate salt after purification on reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 29 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole.(Compound 139)

The title compound was prepared according to General Method 4.2,3,4,5-Tetrahydro-2,8-dimethyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(See Example 1) (200 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324mg, 2.3 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 ml) at 120°C. for 16 h. The reaction was quenched by careful addition of methanolor water and the contents were evaporated to dryness under vacuo. Theresulting crude product was purified by silica gel chromatography(100-200 mesh or 230-400 mesh) by using methanol-dichloromethanegradient and by reverse-phase chromatography (C-18, 500 mm×50 mm, MobilePhase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% Bto 80% B in 30 min, injection vol. 5 mL) to obtain 12.4 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indoleas trifluoroacetate salt.

Example 30 Preparation of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole.(Compound 138)

Preparation of the title compound was carried out according to GeneralMethod 4. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole(See Example 6) (214 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324mg, 2.3 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 ml) at 120°C. for 16 h to obtain 50 mg of2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indoleafter purification by silica gel chromatography (100-200 mesh or 230-400mesh) using methanol-dichloromethane gradient

Example 31 Preparation of2,3,4,5-tetrahydro-2-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole.(Compound 17)

Preparation of the title compound was carried out according to GeneralMethod 4. 2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (SeeExample 3) (186 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324 mg,2.3 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (3 ml) at 120° C.for 16 h to obtain 30 mg of2,3,4,5-tetrahydro-2-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indoleafter purification by silica gel chromatography (230-400 mesh) usingmethanol-dichloromethane gradient.

Example 32 Preparation of5-benzyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole.(Compound 137)

Preparation of the title compound was carried out according to GeneralMethod 5. 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Example 1) (100 mg, 0.5 mmol) and benzyl chloride (0.11 ml, 0.9 mmol)in diisopropylamine (2 mL) were heated at 80° C. for 12 h. The contentswere basified with 1N NaOH and extracted with ethyl acetate. The organiclayer was dried over sodium sulfate and concentrated. The resultingcrude product was purified by silica gel chromatography (230-400 mesh)using methanol-dichloromethane gradient followed by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL) to obtain 20 mg of5-benzyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole as atrifluoroacetate salt.

Example 33 Preparation of5-benzyl-2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole.(Compound 140)

Preparation of the title compound was carried out according to GeneralMethod 5. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole(See Example 6) (100 mg, 0.46 mmol) and benzyl chloride (0.11 ml, 0.9mmol) in diisopropylamine (2 mL) were heated at 80° C. for 12 h toobtain 40 mg of5-benzyl-2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole as atrifluoroacetate salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 34 Preparation of5-benzyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. (Compound16)

Preparation of the title compound was carried out according to GeneralMethod 5. 2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example5) (100 mg, 0.5 mmol), benzyl chloride (158 mg, 1.25 mmol) indiisopropylamine (2 mL) were heated at 80° C. for 12 h to obtain 50 mgof 5-benzyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole astrifluoroacetate salt after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 35 Preparation ofracemic-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol.(Compound 28)

Preparation of the title compound was carried out according to GeneralMethod 6. 3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (SeeExample 1) (2.2 g, 11 mmol), 4-methylstyrene oxide (5.8 g, 44 mmol) andNaH (1.3 g, 32.5 mmol) were heated in DMF (70 mL) at 120° C. for 16 h(overnight). The contents were quenched by methanol and evaporated todryness. The resulting crude product was purified by silica gelchromatography (230-400 mesh) using ethyl acetate-hexane gradient toobtain 1.3 g ofracemic-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol.The free base was converted into its hydrochloride salt by treatment ofethanolic HCl.

Example 36 Preparation ofracemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol.(Compound 29)

Preparation of the title compound was carried out according to GeneralMethod 6. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole(See Example 6) (214 mg, 1 mmol), 4-methylstyrene oxide (1 mL, 7.5 mmol)and NaH (120 mg, 3 mmol) were heated in DMF (4 mL) at 120° C. for 16 h(overnight) to obtain 50 mg ofracemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanolas a trifluoroacetate salt after purification by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 37 Preparation ofracemic-2-(1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol.(Compound 37)

Preparation of the title compound was carried out according to GeneralMethod 6. 2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (SeeExample 3) (400 mg, 2.1 mmol), 4-methylstyrene oxide (2.1 g, 15.7 mmol)and NaH (252 mg, 6.3 mmol) were heated in DMF (5 mL) at 120° C. for 16 hto obtain 75 mg ofracemic-2-(1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanolas a trifluoroacetate salt after purification by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 38 Preparation ofracemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanol.(Compound 8)

Preparation of the title compound was carried out according to GeneralMethod 6. 2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example5) (400 mg, 2.0 mmol), 4-methylstyrene oxide (2.01 g, 15 mmol) and NaH(240 mg, 6 mmol) were heated in DMF (6 mL) at 120° C. for 16 h to obtain120 mg ofracemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanolas a trifluoroacetate salt after purification by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 39 Preparation of ethyl3,4-dihydro-5-(2-(6-methylpyridin-3-yl)ethyl)-8-(pyridin-3-yl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.(Compound 19)

Preparation of the title compound was carried out according to GeneralMethod 7. A mixture of ethyl8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (SeeExample 7) (100 mg, 0.3 mmol), pyridine-3-boronic acid (76 mg, 0.62mmol) and K₃PO₄ (120 mg, 0.57 mmol) in DMF:H₂O (2:1, 3 ml) was purgedwith nitrogen for 30 minutes. PdCl₂(PPh₃)₂ (25 mg, 0.04 mmol) was addedand the reaction was heated at 100° C. for 4 h. The contents wereconcentrated in vacuo and the crude product was purified by silica gelchromatography (230-400 mesh) using ethyl acetate-hexane gradient toobtain 62 mg of ethyl3,4-dihydro-8-(pyridin-3-yl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.This intermediate (25 mg, 0.078 mmol), 2-methyl-5-vinylpyridine (0.120ml, 1 mmol) and NaH (10 mg, 60% dispersion in oil, 0.02 mmol) wereheated in DMSO (0.3 ml) at 100° C. for 48 h, after which methanol wasadded and the contents were concentrated to dryness. The resulting crudeproduct was purified by silica gel chromatography (100-200 mesh or230-400 mesh) using methanol-dichloromethane gradient to obtain 7 mg of3,4-dihydro-5-(2-(6-methylpyridin-3-yl)ethyl)-8-(pyridin-3-yl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.

Example 40 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole.(Compound 20)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (2 g, 12.6 mmol), 2-phenylethyl bromide (1.7 ml, 12.6 mmol) and triethyl amine (1.7 mL, 12.6 mmol)in ethanol (6 ml) were stirred at 25° C. for 1 h after which thecontents were heated at 80° C. for 2 h. The contents were cooled to 25°C., N-methyl-4-piperidone hydrochloride (2.87 g, 18.9 mmol) was addedand heating was continued at 80° C. for 16 h. The contents wereconcentrated in vacuo, basified by adding saturated aqueous NaHCO₃, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated. The crude product was purified bysilica gel chromatography (230-400 mesh) using ethyl acetate-hexanegradient to obtain 150 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole. Thefree base was converted into its oxalate salt by treatment of oxalicacid (1 equiv) in anhydrous THF.

Example 41 Preparation of5-(2-fluorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole.(Compound 34)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (500 mg, 3.1 mmol),2-fluorophenyl ethyl bromide (639 mg, 3.1 mmol), triethyl amine (313 mg,3.1 mmol) and N-methyl-4-piperidone hydrochloride (692 mg, 4.6 mmol)were combined in ethanol (2 ml) to obtain 30 mg of5-(2-fluorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indoleafter purification on neutral alumina using ethyl acetate-hexanegradient. The free base was converted into its oxalate salt by treatmentof oxalic acid (1 equiv) in anhydrous THF.

Example 42 Preparation of5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole.(Compound 163)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (500 mg, 3.1 mmol),1-bromo-2-cyclohexylethane (602 mg, 3 mmol), triethyl amine (303 mg, 3mmol) and N-methyl-4-piperidone hydrochloride (589 mg, 4.5 mmol) werecombined in ethanol (3 ml) to obtain 150 mg of5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indoleafter purification on neutral alumina using ethyl acetate-hexanegradient.

Example 43 Preparation of5-(4-fluorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole.(Compound 33)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (312 mg, 1.9 mmol),4-fluorophenyl ethyl bromide (400 mg, 1.9 mmol), triethyl amine (0.264ml, 1.9 mmol) and N-methyl-4-piperidone hydrochloride (424 mg, 2.8 mmol)were combined in ethanol (3 ml) to obtain 10 mg of5-(4-fluorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indoleafter purification by silica gel chromatography (100-200 mesh or 230-400mesh) using ethyl acetate-hexane gradient. The free base was convertedinto its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrousTHF.

Example 44 Preparation of2-cyclopropyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.(Compound 35)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (500 mg, 3.1 mmol), 2-phenylethyl bromide (0.43 ml, 3.1 mmol), triethyl amine (0.43 ml, 3.1 mmol)and N-cyclopropyl-4-piperidone hydrochloride (650 mg, 4.72 mmol) werecombined in ethanol (3 ml) to obtain 62 mg of2-cyclopropyl-2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indoleafter purification on neutral alumina using ethyl acetate-hexanegradient. The free base was converted into its oxalate salt by treatmentof oxalic acid (1 equiv) in anhydrous THF.

Compound 51 was synthesized according to General Method 8 and asdescribed in Example 44 using appropriately substituted reagents:p-Tolylhydrazine hydrochloride, 5-(2-bromoethyl)-2-methylpyridine,triethyl amine and N-cyclopropyl-4-piperidone hydrochloride werecombined in ethanol.

Example 45 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.(Compound 36)

Preparation of the title compound was carried out according to GeneralMethod 8. 4-Chlorophenylhydrazine hydrochloride (500 mg, 2.79 mmol),2-phenyl ethyl bromide (0.38 ml, 2.79 mmol), triethyl amine (0.39 ml,2.79 mmol) and N-methyl-4-piperidone hydrochloride (623 mg, 4.18 mmol)were combined in ethanol (2 ml) to obtain 15 mg of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt after purification on neutral alumina usingethyl acetate-hexane gradient followed by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Compound 43, Compound 81, Compound 82 and Compound 83 were synthesizedaccording to General Method 8 and as described in Example 45 usingappropriately substituted reagents. Compound 43 Reagents:4-Chlorophenylhydrazine hydrochloride, 1-(2-bromoethyl)-4-methylbenzene,triethyl amine and N-methyl-4-piperidone hydrochloride were combined inethanol. Compound 81 Reagents: 3-Chlorophenylhydrazine hydrochloride,1-(2-bromoethyl)-4-methylbenzene, triethyl amine andN-methyl-4-piperidone hydrochloride were combined in ethanol. Compound82 Reagents: 3-Chlorophenylhydrazine hydrochloride,1-(2-bromoethyl)-4-methylbenzene, triethyl amine andN-methyl-4-piperidone hydrochloride were combined in ethanol. Compound83 Reagents: 2-Chlorophenylhydrazine hydrochloride,1-(2-bromoethyl)-4-methylbenzene, triethyl amine andN-methyl-4-piperidone hydrochloride were combined in ethanol.

Example 46 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-morpholinoethyl)-1H-pyrido[4,3-b]indole.(Compound 186)

Preparation of the title compound was carried out according to GeneralMethod 8. 4-Chlorophenylhydrazine hydrochloride (2 g, 11 mmol),4-(2-bromoethyl)morpholine (2.1 g, 11 mmol), triethyl amine (4.6 ml, 33mmol) and N-methyl-4-piperidone hydrochloride (1.6 g, 11 mmol) werecombined in ethanol (20 ml) to obtain 180 mg of-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-morpholinoethyl)-1H-pyrido[4,3-b]indoleafter purification on silica gel (230-400 mesh) chromatography elutingwith acetone-hexane gradient. The free base was converted into itsdioxalate salt by treatment of oxalic acid (2 equiv) in anhydrous THF.

Example 47 Preparation of8-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole.(Compound 164)

Preparation of the title compound was carried out according to GeneralMethod 8. 4-Chlorophenylhydrazine hydrochloride (1 g, 5.5 mmol),1-bromo-2-cyclohexylethane (0.87 ml, 5.5 mmol), triethyl amine (2.31 ml,16.6 mmol) and N-methyl-4-piperidone hydrochloride (810 mg, 5.5 mmol)were combined in ethanol (10 ml) to obtain 16 mg of8-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indoleafter purification on silica gel (230-400 mesh) chromatography elutingwith acetone-hexane gradient. The free base was converted into itsoxalate salt by treatment of oxalic acid (1 equiv.) in anhydrous THF.

Example 48 Preparation of9-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 187) and7-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole.(Compound 188)

Preparation of the title compounds was carried out according to GeneralMethod 8. 3-Chlorophenylhydrazine hydrochloride (5 g, 27.9 mmol),1-bromo-2-cyclohexylethane (4.37 ml, 27.9 mmol), triethyl amine (11.66ml, 83.7 mmol) and N-methyl-4-piperidone hydrochloride (4 g, 27.9 mmol)were combined in ethanol (30 ml) to obtain9-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indoleand7-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indoleafter on purification on silica gel (230-400 mesh) chromatographyeluting with acetone-hexane gradient. The free base was converted intoits oxalate salt by treatment of oxalic acid (1 equiv.) in anhydrousTHF.

Example 49 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 221)

Preparation of the title compound was carried out according to GeneralMethod 8. 4-Methylphenylhydrazine hydrochloride (2 g, 12.6 mmol),1-(2-bromoethyl)pyrrolidine hydrobromide (8.1 g, 31.5 mmol), triethylamine (17.5 ml, 126 mmol) and N-methyl-4-piperidone hydrochloride (1.87g, 12.6 mmol) were combined in ethanol (15 ml) to obtain 180 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indoleafter on purification on silica gel (230-400 mesh) chromatographyeluting with acetone-hexane gradient. The free base was converted intoits dioxalate salt by treatment of oxalic acid (2 equiv.) in anhydrousTHF.

Example 50 Preparation of3,4-dihydro-3-hydroxy-2,8-dimethyl-5-phenethyl-2H-pyrido[4,3-b]indol-1(5H)-one.(Compound 215)

The title compound was prepared according to the synthetic schemeoutlined above and detailed below.

Example 50A Preparation of 1-phenethyl-1-p-tolylhydrazine

p-Tolylhydrazine hydrochloride (10.0 g, 63 mmol) was suspended in EtOH(45 mL). To this suspension was added triethylamine (9.0 mL, 63 mmol)drop-wise over a period of 5-10 minutes. The reaction mixture wasstirred for additional 10 minutes. Phenethyl bromide (9 mL, 63 mmol) wasadded drop-wise at 25° C. over a period of 10 to 15 minutes. Thereaction mixture was heated at 80° C. for 2 h at which point thereaction was found complete by TLC and LC-MS. The reaction mixture wasconcentrated under reduced pressure, the residue was suspended insaturated aqueous NaHCO₃ (pH 9) and extracted with ethyl acetate (100mL×2). The organic layer was separated, dried (Na₂SO₄) and concentratedto obtain crude product as a dark brown oil (14 g). Purification ofcrude product by flash column chromatography (silica gel, 230-400 mesh,eluent: 8-10% ethyl acetate-hexanes) furnished 3.7 g of pure product asyellow oil. Yield: 26% (unoptimized).

Example 50B Preparation of ethyl2,5-dimethyl-1-phenethyl-1H-indole-3-carboxylate

1-phenethyl-1-p-tolylhydrazine (3.7 g, 16.3 mmol) was dissolved inethanolic HCl (40 mL, pH of the solution was acidic) and ethylacetoacetate (2.0 mL, 16.3 mmol) was added to it. The reaction mixturewas heated at 110° C. for 1.5 h at which point the reaction was foundcomplete by TLC and LC-MS. The reaction mixture was concentrated underreduced pressure, the residue was suspended in saturated aqueous NaHCO₃(pH 9) and extracted with ethyl acetate (100 mL×2). The organic layerwas separated, dried (Na₂SO₄) and concentrated to obtain a crude productas dark brown oil. Purification of crude product by flash columnchromatography (silica gel, 230-400 mesh, eluent: 5-10% ethylacetate-hexanes) furnished 3.2 g of pure product as yellow solid.

Example 50C Preparation of2,5-dimethyl-1-phenethyl-1H-indole-3-carboxylic acid

A mixture of ethyl 2,5-dimethyl-1-phenethyl-1H-indole-3-carboxylate (500mg) and NaOH (500 mg) in ethanol (15 mL) was heated at 100° C. for 3 hat which point the reaction was found complete by TLC and LC-MS. Thereaction mixture was acidified to pH 4-5 by adding ethanolic HCl andevaporated under reduced pressure. The residue (1 g), that alsocontained NaCl generated during NaOH neutralization, was carried forwardto next reaction without any purification.

Example 50D Preparation of 2,5-dimethyl-1-phenethyl-1H-indole-3-carbonylchloride

To a stiffing solution of the carboxylate acid (1.6 g crude product overprevious two examples, considered as approx. 2.5 mmol) in anhydrousCH₂Cl₂ (15 ml) at 0° C. was added a drop of DMF, followed by oxalylchloride (0.6 mL, 6.9 mmol) via syringe. After stiffing at 0° C. for 15minutes, the ice bath was removed and the mixture was stirred at ambienttemperature for 55 minutes. The mixture is concentrated to dryness underreduced pressure (protected from moisture) to obtain the crude acidchloride that was stored under nitrogen, and used in the next examplewithout any purification.

Example 50E Preparation ofN,2,5-trimethyl-1-phenethyl-1H-indole-3-carboxamide

The acid chloride from example 50D was dissolved in CH₂Cl₂ (10 ML) andcooled to 0° C. To this was added in excess, a solution of methylaminein DCM (50 ml). The reaction was slowly warmed to and stirred at 25° C.for additional 1 h at which point the reaction was found complete by TLCand LC-MS. The solution was partitioned between CH₂Cl₂ and water. Theorganic layer was separated, dried over Na₂SO₄ and concentrated underreduced pressure to obtain 650 mg of light brown solid.

Example 50F Preparation of3,4-dihydro-3-hydroxy-2,8-dimethyl-5-phenethyl-2H-pyrido[4,3-b]indol-1(5H)-one

A solution of amide (125 mg, 0.41 mmol) in 3 mL of tetrahydrofuran wascooled to −25 to −30° C. (under N₂) and a solution of n-BuLi in hexanes(1 mL of 1.6 M, 1.6 mmol) was added at such a rate as to maintain theinternal temperature between −25 to −30° C. The resulting deep redsolution was stirred at −25 to −30° C. for 40 minutes and DMF (0.1 mL)was added at −25 to −30° C. After the addition was complete, thesolution was stirred at −25 to −30° C. for 30 minutes. Hydrochloric acid(0.3 mL of 6 N) was slowly added, keeping the temperature below 5° C.(pH 3-4). The mixture was concentrated in vacuo to obtain 90 mg ofyellow semi-solid. The product was triturated with diethylether-hexanes, followed by diethyl ether and filtered to obtain 30 mg ofyellow solid.

Compound 216 was prepared according General Method 8 by following ananalogous procedure described for Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole(Example 47) using p-tolylhydrazine hydrochloride,5-(2-bromoethyl)-2-methylpyridine and 1-methylpiperidine-2,4-dione.

Example 51 Preparation of (Compound 47) and (Compound 53)

The title compounds were prepared according to General Method 8 usingthe appropriately substituted reagents: (Compound 47) Reagents:4-(trifluoromethyl)phenylhydrazine hydrochloride,1-(2-bromoethyl)-4-methylbenzene, triethyl amine andN-methyl-4-piperidone hydrochloride in ethanol and (Compound 53).Reagents: 4-(trifluoromethyl)phenylhydrazine hydrochloride,5-(2-bromoethyl)-2-methylpyridine, triethyl amine andN-methyl-4-piperidone hydrochloride in ethanol.

Example 52 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(piperidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 224)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (2.0 g, 12.6 mmol),1-(2-chloroethyl)-piperidine monohydrochloride (2.32 g, 12.6 mmol),triethyl amine (5.3 ml, 37.8 mmol) and N-methyl-4-piperidonehydrochloride (1.87 g, 2.1 mmol) were taken in ethanol (30 ml) to obtain180 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(piperidin-1-yl)ethyl)-1H-pyrido[4,3-b]indoleafter purification on silica gel (230-400 mesh) chromatography elutingwith acetone-hexane gradient. The free base was converted intobis(oxalate) salt by treatment of oxalic acid (2 equiv) in anhydrousTHF.

Example 53 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole.(Compound 225)

Preparation of the title compound was carried out according to GeneralMethod 8. 4-Chlorophenylhydrazine hydrochloride (9 g, 50 mmol),5-(2-bromoethyl)-2-methylpyridine (10 g, 50 mmol), triethyl amine (21ml, 150 mmol) and N-methyl-4-piperidone hydrochloride (7.5 g, 50 mmol)were taken in ethanol (100 ml) to obtain 390 mg of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indoleafter on purification on silica gel (230-400 mesh) chromatographyeluting with methanol-dichloromethane gradient followed by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 54 Preparation of tert-butyl1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate.(Compound 226) Example 54A Preparation of3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5 yl)propanoic acid

Preparation of ethyl3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate wasaccomplished using tolylhydrazine hydrochloride (20 g, 126 mmol),3-bromoethyl propionate (22.8 g, 126 mmol), triethyl amine (38.1 g, 378mmol) and N-methyl-4-piperidone hydrochloride (18.77 g, 126 mmol) inethanol (200 ml) to obtain 1.5 g of ethyl3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoateafter purification on neutral alumina chromatography eluting withdichloromethane-hexane gradient.

Example 54B Preparation of3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid

A mixture of ethyl3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate(See Example 54A) (1.5 g) and NaOH (3N, 30 ml) in ethanol (30 ml) wasstirred at 50° C. for 3 h after which it was cooled to room temperatureand neutralized with concentrated HCl. The solvent was removed underreduced pressure to obtain crude3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoicacid.

Example 54C

The title compound, tert-butyl1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate,was obtained as follows.3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid(500 mg, 1.8 mmol) (See Example 54B) was stirred with tert-butylpiperidin-4-ylcarbamate (0.366 ml, 1.8 mmol), EDCI-HCl (0.35 g, 1.8mmol) and triethyl amine (0.253 ml, 1.8 mmol) in dichloromethane (20 ml)to obtain 50 mg of tert-butyl1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamateas a trifluoroacetate salt after purification on neutral aluminachromatography eluting with methanol-dichloromethane gradient followedby reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL).

Example 55 Preparation of 2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.(Compound 227)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (10 g, 63 mmol), 2-phenyl ethylbromide (11.6 g, 63 mmol), triethyl amine (19.4 g, 189 mmol) and2,2,2-trichloroethyl 4-oxopiperidine-1-carboxylate (452 mg, 2 mmol) weretaken in ethanol (10 ml) at 90° C. for 3 h to obtain 200 mg of2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylateafter purification on silica gel (230-400 mesh) chromatography elutingwith methanol-dichloromethane gradient.

Compound 235 can be made according to the procedure described in Example55 using appropriately substituted reagents.1-(2-(6-methylpyridin-3-yl)ethyl)-1-p-tolylhydrazine (500 mg) andN-Troc-piperidone (560 mg) were mixed in 15 mL ethanolic HCl and stirredfor 20 min. The volatiles were removed under reduced pressure, theresidue was taken in ethanol (5 mL) and the solution was heated at 90°C. for 3 h (the reaction was monitored by LCMS and TLC). The reactionmixture was cooled to 25° C. and evaporated under reduced pressure. Theresidue was basified with satd. aq. NaHCO₃ and extracted with ethylacetate. The combined ethyl acetate layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain the crude product. Thecrude product was purified by flash chromatography on silica gel(eluent: hexane to 10% acetonehexane gradient) to obtain 100 mg ofproduct as light yellow oil. TLC Rf 0.2 in 20% acetone-hexane.

Example 56 Preparation of2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.(Compound 228)

A mixture of 2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(100 mg, 0.2 mmol) and Zn dust (120 mg, 1.9 mmol) in acetic acid (1.2ml) was stirred at 25° C. for 2 h. The reaction mixture was basifiedwith saturated aqueous NaHCO₃ and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and evaporated toobtain 30 mg of2,3,4,5-tetrahydro-8-methyl-5-phenethyl-1H-pyrido[4,3-b]indole afterpurification on silica gel (230-400 mesh) chromatography eluting withmethanol-dichloromethane gradient.

Example 57 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indoleN′-oxide. (Compound 229)

2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(98 mg, 3.1 mmol) was stirred with hydrogen peroxide (30% in water, 0.2ml) in glacial acetic acid (1.2 ml) at 865-70° C. for 20 h to obtain 76mg of corresponding N,N′-dioxide. To this intermediate (76 mg, 0.21mmol) in acetic acid (0.3 ml) and methanol (2 ml) was added sodiumbisulphate (40% in water, 0.2 ml) and the reaction mixture was stirredat 0° C. for 0.5 h. The reaction mixture was basified with saturatedaqueous NaHCO₃ and extracted with ethyl acetate to obtain 50 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indoleN′-oxide.

Example 58A Preparation of 2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (5 g, 31.5 mmol),5-(2-bromoethyl)-2-methylpyridine (6.3 g, 31.5 mmol), triethyl amine (13ml, 94.5 mmol) and 2,2,2-trichloroethyl 4-oxopiperidine-1-carboxylate(563 mg, 2 mmol) were taken in ethanol (15 ml) to obtain 100 mg of2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylateafter purification on silica gel (230-400 mesh) chromatography elutingwith acetone-hexane gradient.

Example 58B Preparation of2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole

A mixture of 2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(100 mg, 0.2 mmol) and Zn dust (120 mg, 1.9 mmol) in acetic acid (1.2ml) was stirred at 25° C. for 12 h. The reaction mixture was basifiedwith saturated aqueous ammonia and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and evaporated toobtain 75 mg of2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indoleafter purification on silica gel (230-400 mesh) chromatography elutingwith methanol-dichloromethane gradient. The free base was converted intoits oxalate salt by treatment of oxalic acid (1 equiv.) in anhydrousTHF.

Example 59 Preparation of1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8dimethylpyrido[4,3-b]indol-5-yl)propan-1-one.(Compound 231)

Tert-butyl1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate(See Example 54) (50 mg) was stirred with trifluoroacetic acid (2 ml) indichloromethane (2 ml) for 16 h at 25° C. to obtain 10 mg of1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-oneas a trifluoroacetate salt after purification by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 60 Preparation of4-bromo-1,2-dihydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indol-3(5H)-one.(Compound 232)

Preparation of the title compound was carried out according to GeneralMethod 8. p-Tolylhydrazine hydrochloride (1.27 g, 8 mmol),5-(2-bromoethyl)-2-methylpyridine (1.6 g, 8 mmol), triethyl amine (3.5ml, 24 mmol) and 1-methylpiperidine-2,4-dione (4.2 g, 8 mmol) were takenin ethanol (25 ml) to obtain 40 mg of1,2-dihydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indol-3(5H)-oneafter purification on silica gel (230-400 mesh) chromatography elutingwith methanol-dichloromethane gradient. To this intermediate (25 mg,0.07 mmol) was added N-bromo succinamide (26 mg, 0.1), andazobisisobutyronitrile (1 mg) in carbon tetrachloride (10 ml) and thereaction mixture was heated at 80° C. for 12 h to obtain 5 mg of4-bromo-1,2-dihydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indol-3(5H)-oneas a trifluoroacetate salt after purification by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 61 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)propyl)-1H-pyrido[4,3-b]indole.(Compound 233) Example 61A Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole

A mixture of2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole(obtained by General Method 8; p-tolylhydrazine hydrochloride (600 mg,3.7 mmol), propargyl bromide (80 wt % solution in toluene, 0.34 ml, 3.7mmol), triethyl amine (1.5 ml, 11.3 mmol) and N-methyl-4-piperidonehydrochloride (316 mg, 2.1 mmol) were taken in ethanol (15 ml) to obtain80 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indoleafter purification on silica gel (230-400 mesh) chromatography elutingwith methanol-dichloromethane gradient) (150 mg, 0.6 mmol),2-bromopyridine (0.06 ml, 0.6 mmol), dichlorobis(triphenylphosphine)palladium (8 mg, 0.012 mmol), CuI (1 mg, 0.006 mmol), and triethylamine(0.01 ml 0.071 mmol) in acetonitrile (5 ml) was heated at 80° C. for 1.5h to obtain 108 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indoleafter purification by reverse-phase chromatography (C-18, 500 mm×50 mm,Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 61B

2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole(See Example 61A) (20 mg, 0.06 mmol) was hydrogenated in methanol (2 ml)with 10% Pd—C (10 mg) at 1 atm of hydrogen to obtain 5 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)propyl)-1H-pyrido[4,3-b]indoleafter purification on neutral alumina chromatography eluting withmethanol-dichloromethane gradient. The free base was converted into itsdiHCl salt by treatment of ethanolic HCl.

Example 62 Preparation of5-(2-fluorophenethyl)-2,3,4,5-tetrahydro-8-iodo-2-methyl-1H-pyrido[4,3-b]indole.(Compound 89)

Preparation of the title compound was carried out according to GeneralMethod 8. 4-Iodophenylhydrazine hydrochloride (500 mg, 2.1 mmol),2-fluorophenethylbromide (0.3 ml, 2.1 mmol), triethyl amine (0.8 ml, 6.3mmol) and N-methyl-4-piperidone hydrochloride (312 mg, 2.1 mmol) weretaken in ethanol (10 ml) to obtain 5 mg of5-(2-fluorophenethyl)-2,3,4,5-tetrahydro-8-iodo-2-methyl-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt after purification by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 63 Preparation of1,2-dihydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indol-3(5H)-one.(Compound 195)

Preparation of the title compound was carried out according to GeneralMethod 8 by following an analogous procedure described for Preparationof 2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole(Example 47) using p-tolylhydrazine hydrochloride,5-(2-bromoethyl)-2-methylpyridine and 1-methylpiperidine-2,4-dione.

Example 64 Preparation of8-(trifluoromethyl)-2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole.(Compound 80)

Preparation of the title compound was carried out according to GeneralMethod 8 by following an analogous procedure described for Preparationof 2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole(See Example 47) using 4-(trifluoromethyl)phenylhydrazine, 2-phenylethyl bromide and N-methyl-4-piperidone hydrochloride.

Example 65 Preparation of5-(4-chlorophenethyl)-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole.(Compound 45)

Preparation of the title compound was carried out according to GeneralMethod 8 by following an analogous procedure described for Preparationof 2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole(See Example 47) using 4-chlorophenylhydrazine hydrochloride,4-chlorophenethyl bromide and N-methyl-4-piperidone hydrochloride.

Example 66 Preparation of5-(4-fluorophenethyl)-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole.(Compound 162)

Preparation of the title compound was carried out according to GeneralMethod 8 by following an analogous procedure described for Preparationof 2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole(See Example 47) using 4-chlorophenylhydrazine hydrochloride,4-fluorophenethyl bromide and N-methyl-4-piperidone hydrochloride.

Example 67 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)ethanone(Compound 236)

A mixture of ethyl2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate(200 mg) and piperidine (2 ml) was heated at 120° C. for 8 h to obtain 5mg of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)ethanoneas TFA salt after purification on silica gel (230-400 mesh)chromatography eluting with methanol-dichloromethane gradient followedby reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL).

Example 68 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)ethanone(Compound 237)

A mixture of ethyl2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate(200 mg) and 4-methylpiperidine (2 ml) was heated at 120° C. for 8 h toobtain 40 mg of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)ethanoneafter purification on neutral alumina chromatography eluting withmethanol-dichloromethane gradient. The free base was converted into itsoxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.

Example 69 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-morpholinoethanone(Compound 238)

A mixture of ethyl2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate(200 mg) and morpholine (2 ml) was heated at 120° C. for 15 h to obtain27 mg of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-morpholinoethanoneafter purification on neutral alumina chromatography eluting withmethanol-dichloromethane gradient. The free base was converted into itsoxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.

Example 70 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-thiomorpholinoethanone(Compound 239)

A mixture of ethyl2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate(200 mg) and thiomorpholine (2 ml) was heated at 120° C. for 15 h toobtain 38 mg of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-thiomorpholinoethanoneafter purification on neutral alumina chromatography eluting withmethanol-dichloromethane gradient. The free base was converted into itsoxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.

Example 71 Preparation of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)propan-1-one(Compound 240)

A mixture of ethyl3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate(100 mg) and pyrrolidine (2 ml) was heated at 120° C. for 3 h to obtain39 mg of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)propan-1-oneafter purification on neutral alumina chromatography eluting withmethanol-dichloromethane gradient. The free base was converted into itsoxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.

Example 72 Preparation of1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-one(Compound 231)

tert-butyl1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate(50 mg) was stirred with trifluoroacetic acid (2 ml) in dichloromethane(2 ml) for 16 h at 25° C. to obtain 10 mg of1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-oneas di-TFA salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 76 Preparation of Compound 241

Dimebon dihydrochloride (100 mg) was mixed with SeO₂ (138 mg) inpyridine (1 mL) and the reaction mixture was heated at 80° C. for 48 h.The reaction mixture was concentrated under reduced pressure and theresulting crude product was purified by reverse phase chromatography toobtain 28 mg of product.

Example 77 Preparation of Compound 189

The title compound was prepared according to General Method 8 using thefollowing reagents: 4-chlorophenylhydrazine, 1-(2-chloroethyl)piperidinehydrochloride, N-methyl-4-piperidone.

Example 78 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanone(Compound 243)

A mixture of ethyl2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate(100 mg) and pyrrolidine (1 ml) was heated at 120° C. for 15 h to obtain59 mg of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanoneafter purification on neutral alumina chromatography eluting withmethanol-dichloromethane gradient. The free base was converted into itsoxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.

Example 79 Preparation of Compound 244

The title compound was prepared using the following reagents:4-chlorophenylhydrazine hydrochloride, N-methyl-4-piperidone, ethylbromoacetate, piperazine.

Example 80 Preparation of Compound 245

The title compound was prepared using the following reagents:4-chlorophenylhydrazine hydrochloride, N-methyl-4-piperidone, ethylbromoacetate, 2,6-dimethylpiperazine.

Example 81 Preparation of Compound 246

The title compound was prepared using the following reagents:4-chlorophenylhydrazine hydrochloride, N-methyl-4-piperidone, ethylbromoacetate, 2-oxopiperazine.

Example 82 Preparation of Compound 247

The title compound was prepared according to General Method 8 using thefollowing reagents: p-Tolylhydrazine hydrochloride,N-methyl-4-piperidone, 4-methoxyphenethyl bromide.

Example 83 Preparation of Compound 248

The title compound was prepared using the following reagents:4-chlorophenylhydrazine hydrochloride, N-methyl-4-piperidone, ethylbromoacetate, 1-isopropylpiperazine

Example 84 Preparation of Compound 249

The title compound was prepared according to General Method 8 using thefollowing reagents: 4-fluorophenylhydrazine hydrochloride,N-methyl-4-piperidone, 4-chlorophenethyl bromide.

Example 85 Preparation of Compound 250

The title compound was prepared according to General Method 1 using thefollowing reagents: 4-chlorophenylhydrazine hydrochloride,N-methyl-4-piperidone, 2-(trifluoromethyl)-5-vinylpyridine.

2 g of 5-bromo-2-(trifluoromethyl)pyridine was dissolved in DMF:THF(3:1, 12 mL). vinyltributyltin (3 g) and tetrakis(triphenylphosphine)palladium (135 mg) were added to this solution. Thereaction mixture was degassed and purged with nitrogen for 5 min andthen heated at 100° C. for 2 h. at which point the reaction was foundcomplete (monitored by TLC). The reaction mixture was diluted with waterand extracted with ethyl acetate. The combined organic layer was driedover anhydrous sodium sulfate and evaporated under reduced pressure(Caution: product may be volatile) and the residue was purified by SiO₂chromatography (100-200 mesh, eluent: hexane-ethyl acetate gradient).The requisite fractions were concentrated below 40° C. under reducedpressure to obtain 20.3 g of 2-(trifluoromethyl)-5-vinylpyridine as oil.

222 mg 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole wasdissolved in NMP (0.6 mL). Powdered KOH (196 mg) was added to thissolution, and the reaction mixture was stirred for 10 min at 25° C.Finally, 2-(trifluoromethyl)-5-vinylpyridine (190 mg) was added and thereaction mixture was heated in sealed tube at 45° C. for 30 min. Thereaction was monitored by LCMS. After this period, the reaction mixturewas cooled to 25° C. and diluted with satd. aqueous NaCl (5 mL). Theproduct was extracted with ethyl acetate. The combined organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure and the residue was purified by SiO₂ chromatography (100-200mesh, eluent: dichloromethane-methanol gradient). The requisitefractions were concentrated below 40° C. under reduced pressure toobtain 160 mg of product. The free base was converted into its oxalatesalt by treatment of oxalic acid (1 equiv) in anhydrous THF.

Example 86 Preparation of Compound 251

The title compound was prepared using the following reagents:p-Tolylhydrazine hydrochloride, N-methyl-4-piperidone, ethylbromoacetate, 4-methylpiperidine.

Example 87 Preparation of Compound 252

The title compound was prepared according to General Method 1 using thefollowing reagents: p-Tolylhydrazine hydrochloride,N-methyl-4-piperidone, 2-(trifluoromethyl)-5-vinylpyridine.

2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride(203 mg) was dissolved in NMP (2.5 mL). Powdered KOH (463 mg) was addedto this solution, and the reaction mixture was stirred for 10 min at 25°C. Finally, 2-(trifluoromethyl)-5-vinylpyridine (300 mg) was added andthe reaction mixture was stirred at 25° C. for 4 h. The reaction wasmonitored by LCMS. After this period, the reaction mixture was cooled to25° C. and diluted with satd. aqueous NaCl (5 mL). The product wasextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure and theresidue was purified by SiO₂ chromatography (100-200 mesh, eluent:dichloromethane-methanol gradient). The requisite fractions wereconcentrated below 40° C. under reduced pressure to obtain 140 mg ofproduct. The free base was converted into its oxalate salt by treatmentof oxalic acid (1 equiv) in anhydrous THF.

Example 88 Preparation of Compound 253

The title compound was prepared according to General Method 8 using thefollowing reagents: 4-fluorophenylhydrazine hydrochloride,N-methyl-4-piperidone, 4-fluorophenethyl bromide.

Example 89 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole

A mixture of2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole(150 mg, 0.6 mmol), 3-bromopyridine (0.6 ml, 0.6 mmol),dichlorobis(triphenyl-phosphine) palladium (8 mg, 0.012 mmol), CuI (1mg, 0.006 mmol), and triethylamine (0.01 ml 0.071 mmol) in acetonitrile(5 ml) was heated at 80° C. to obtain 108 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indoleafter purification by reverse-phase chromatography (C-18, 500 mm×50 mm,Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)propyl)-1H-pyrido[4,3-b]indole

2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole(20 mg, 0.06 mmol) was hydrogenated in methanol (2 ml) with 10% Pd—C (10mg) at 1 atm of hydrogen to obtain 5 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)propyl)-1H-pyrido[4,3-b]indoleafter purification on neutral alumina chromatography eluting withmethanol-dichloromethane gradient. The free base was converted into itsHCl salt by treatment of ethanolic HCl.

Example 90 Preparation of Compound 255

2,5-Dibromopyridine (5 g) was dissolved in toluene (30 mL) and thesolution was cooled to −75° C. BuLi was added drop wise to this solutionover a period of 20 min. The reaction was maintained at −75° C. for 2 h.Dry ice (200 g) was added and the reaction mixture was slowly allowed towarm to 25° C. The reaction mixture was evaporated to dryness, theresidue was dissolved in water (25 mL) and the pH was adjusted to 7 byadding conc. HCl. The solid product was filtered and washed with waterfollowed by diethyl ether. Yield 3 g. TLC Rf 0.1 in 50% ethylacetate-hexane.

5-Bromopyridine-2-carboxylic acid (10 g) was dissolved in 260 mL MeOH.SOCl₂ (26 mL) was added dropwise to this solution over a period of 10min (Caution: Exothermic reaction). The reaction mixture was heated to65° C. for 2 h at which point the reaction was found complete by TLC (analiquot was evaporated to dryness, the residue taken up in satd. aq.NaHCO₃ and extracted with ethyl acetate). The reaction mixture wasevaporated to dryness. The residue was basified with satd. aq. NaHCO₃and extracted with ethyl acetate. The combined ethyl acetate layer wasdried (Na₂SO₄) and evaporated under reduced pressure to obtain 9.2 g ofthe solid product. TLC Rf 0.5 (40% Ethyl acetate-hexane).

4 g of methyl 5-bromopyridine-2-carboxylate was dissolved in 160 mLdioxane. vinyltributyltin (11.7 g) was added to this solution at 25° C.,followed by addition of dichlorobis (triphenylphosphine)palladium (1.5g). The reaction mixture was degassed and purged with nitrogen for 5 minand then heated at 100° C. for 2 h. at which point the reaction wasfound complete (monitored by TLC). The reaction mixture was evaporatedunder reduced pressure (Caution: product may be volatile) and theresidue was purified by SiO₂ chromatography (100-200 mesh, eluent:hexane-50% ethyl acetate hexane gradient). The requisite fractions wereconcentrated below 40° C. under reduced pressure to obtain 2 g ofproduct as pale yellow oil (solid at −20° C.). TLC Rf 0.3 in 40%EA-Hexane.

2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride(710 mg) was dissolved in NMP (7.5 mL). Powdered KOH (1.62 g) was addedto this solution, and the reaction mixture was stirred for 10 min at 25°C. Finally, 5-vinyl pyridine-2-carboxylic acid methyl ester (977 mg) wasadded dropwise over 5 min and the reaction mixture was heated in sealedtube at 100° C. for 24 h. The reaction was monitored by LCMS. After thisperiod, the reaction mixture was cooled to 25° C. and diluted with water(7 mL). The pH of the resulting solution was adjusted to 4-5 by additionof formic acid. The resulting solution was directly subjected topurification by reverse-phase HPLC. The requisite fractions containingproduct were pooled and lyophilized (Caution: compound may be heatsensitive) to obtain 370 mg of product as TFA salt with 84% HPLC purity(with 16% contamination of unreacted carboline). The purity was enhancedto 98.5 by a second purification on reverse phase HPLC.

Example 91 Preparation of Compound 256

Methyl 4-aminobenzoate (5.0 g, 0.0331 moles) was taken up in conc. HCl(50 mL) and cooled to 0° C. Sodium nitrite (2.5 g, 0.0331 moles)solution in water was added at 0° C. over 30 minutes and stirred at RTfor 90 min. Tin chloride (19.40 g, 0.0927 moles) in HCl (100 mL) wasadded drop wise at 0° C. and stirred at RT for 2 hr. The reaction wasfiltered and the solid obtained was washed with diethyl ether and driedon a rotary evaporator to give 6.2 g, 92.53% yield of Methyl4-hydrazinylbenzoate as a white solid.

Methyl 4-hydrazinylbenzoate (1 g, 0.005 moles) and5-(2-bromoethyl)-2-methylpyridine (1 g, 0.005 moles) was taken up intriethylamine (2.1 mL) and stirred at RT for 1 hr. The reaction washeated at 100° C., overnight. LCMS analysis of the reaction mixturesshows the formation of product. The reaction mixture was concentrated,water (20 mL) was added to the reaction mixture and the mixtureextracted with ethyl acetate. The crude product was dissolved in ethylacetate and purified by column chromatography using neutral alumina,using 100% ethyl acetate as the eluent. After chromatography 400 mg ofMethyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate wasobtained, 28.5% yield.

Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate (0.1 g,0.350 mmoles) and 1-methylpiperidin-4-one (0.052 g, 0.350 mmoles) wastaken up in 1M HCl (4 mL) and heated at 100° C. for 18 hr. LCMS of thereaction mixture shows the formation of the product. The reactionmixture was concentrated and purified by reverse phase HPLC to give 5 mgof2-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid, as a white solid, 4% yield.

Example 92 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanone(Compound 257)

A mixture of ethyl2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (100mg) and pyrrolidine (1 ml) was heated at 100° C. for 15 h to obtain 60mg of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanoneas off white solid after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 93 Preparation of2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole2-oxide

Dimebon (500 mg) was dissolved in 10 mL dichloromethane. To this wasadded a solution of mCPBA (65%, 536 mg) in 5 mL dichloromethane dropwise at 25 deg C. The reaction mixture was stirred at 25 deg C. for 24 hat which point it was found complete (by TLC and LCMS). The solvent wasremoved under reduced pressure (below 30 deg C.) and the residue waspurified by column chromatography on neutral alumina eluting withmethanol-dichloromethane gradient to obtain 220 mg of product as lightbrown oil. TLC Rf 0.5 in 5% MeOH-DCM. This compound also exhibited thefollowing inhibition profile:

Adren. Adren. Adren. Dop. Hist. Hist. Ser. Ser. Ser. Ser. alpha1Dalpha2A alpha2B D2L H1 H2 5-HT2A 5-HT2C 5-HT6 5-HT7 19 1 36 68 19 4 9 1135

Example 94 Preparation of 2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(Compound 259)

1-(2-(6-methylpyridin-3-yl)ethyl)-1-p-tolylhydrazine (500 mg) andN-Troc-piperidone (560 mg) were mixed in 15 mL ethanolic HCl and stirredfor 20 min. The volatiles were removed under reduced pressure, theresidue was taken in ethanol (5 mL) and the solution was heated at 90deg C. for 3 h (the reaction was monitored by LCMS and TLC). Thereaction mixture was cooled to 25 deg C. and evaporated under reducedpressure. The residue was basified with satd. aq. NaHCO3 and extractedwith ethyl acetate. The combined ethyl acetate layer was dried overNa2SO4 and concentrated under reduced pressure to obtain the crudeproduct. The crude product was purified by flash chromatography onsilica gel (eluent: hexane to 10% acetonehexane gradient) to obtain 100mg of product as light yellow oil. TLC Rf 0.2 in 20% acetone-hexane.

Example 95 Preparation of2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 230)

2,2,2-trichloroethyl3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1Hpyrido[4,3-b]indole2(5H)-carboxylate (100 mg) was dissolved in glacial AcOH (1.2 mL) andthe solution was stirred at 25 deg C. for 10 min. To this solution Zndust (121 mg) was added in portions at 25 deg C. after which thereaction mixture was stirred at 25 deg C. overnight. The reactionmixture was cooled to 0 deg C. and pH was adjusted to 8 with aq. NH3.The reaction mixture was extracted with ethyl acetate, the combinedethyl acetate layer was dried over sodium sulfate and concentrated toobtain 75 mg of product with 87% HPLC purity. The product (free base)was converted into oxalate salt by treatment of 30 mg oxalic acid in 2mL THF. Filtration of the resulting suspension furnished product.

Example 96 Preparation of2-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid Compound 261

Methyl 4-hydrazinylbenzoate (5.0 g, 0.0331 moles) was taken up in 50 mLof conc. HCl and cooled to 0 degrees C. Sodium nitrite (2.5 g, 0.0331moles) solution in water, was added at 0 degrees C. over 30 minutes andstirred at RT for 90 min. Tin chloride (19.40 g, 0.0927 moles) in 100 mLHCl was added drop wise at 0 degrees C. and stirred at RT for 2 hr. Thereaction was filtered and the solid obtained was washed with diethylether and dried on a rotary evaporator to give 6.2 g, 92.53% yield ofMethyl 4-hydrazinylbenzoate as a white solid.

Methyl 4-hydrazinylbenzoate (1 g, 0.005 moles) and5-(2-bromoethyl)-2-methylpyridine (1 g, 0.005 moles) was taken up in 2.1mL of triethylamine and stirred at RT for 1 hr. The reaction was thenheated at 100 degrees C., overnight. LCMS analysis of the reactionmixtures shows the formation of product. Reaction mixture wasconcentrated, water (20 mL) was added to the reaction mixture and themixture extracted with ethyl acetate. The crude product was dissolved inethyl acetate and purified by column chromatography using neutralalumina, using 100% ethyl acetate as the eluent. After chromatography400 mg of Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoatewas obtained, 28.5% yield.

Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate (0.1 g,0.350 mmoles) and 1-methylpiperidin-4-one (0.052 g, 0.350 mmoles) wastaken up in 4 mL 1M HCl and heated at 100 degrees C. for 18 hr. LCMS ofthe reaction mixture shows the formation of the product. The reactionmixture was concentrated and purified by reverse phase HPLC.¹ to give 5mg of2-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid, as a white solid, 4% yield. Batch Size—800 mg, Purity:—˜3% Sincethe compound is highly Polar First Purification Was carried on prep HPLCusing Water (0.05% TFA) as eluent. Method Details: Sample preparation:Compound dissolved in Milli-Q Water (4.0 mL) Clear Brown solutionColumn: YMC ODS A, 500 mm×30 mm×10μ Flow: 30 mL/min Wavelength:monitored at 220 nm & 254 nm. Mobile Phase Mobile Phase A: 0.05% TFA inwater Mobile Phase B: 0.05% TFA in Acetonitrile Gradient Program 0% Bfor 15 min 0% B to 50% B in 27 min. Column Washed with 100% methanol.Collected fractions were lyophilized. Lyophilized solid having purity80% were dissolved in 250 μL and analyzed by following method. (Methoddetails for analysis: Column Zorbax cyano, 150 mm×4.6×3.50, Flow: 1.2mL/min, inj. Vol: 10.0 μL, Wavelength: 220 nm & 254 nm, GradientProgram: 0% B to 50% B in 5 min hold for 2 min 7.01 min to 10.0 min 0% BSecond purification Total Vol: 250 μL Column: Zorbax cyano, 150mm×4.6×3.5μ), Flow: 1.2 mL/min, inj. Vol: 10.0 μL, Wavelength: 220 nm &254 nm, Mobile Phase Mobile Phase A: 0.05% TFA in water Mobile Phase B:0.05% TFA in Acetonitrile Isocratic program 8% B for 5 min. number ofinjections: 25 Purity of pooled fraction: 98% Collected fractions werelyophilized Purity after lyophilization: 92.07%

Example 97 Preparation of2,3,4,5-tetrahydro-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-8-carboxylicacid (Compound 274)

A mixture of Methyl4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate hydrochloride(0.15 gm, 0.447 mol), piperidone (0.13 gm, 1.34 mol) and 7% sulfuricacid in dioxane (5 mL) was heated at 100 deg C. for 2 h. Reaction masswas cooled and concentrated under reduced pressure to give crude2,3,4,5-tetrahydro-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-8-carboxylicacid (LCMS; 44% of desired peak) as a brown colored oil which issubmitted for purification by preparative HPLC.

Example 98 Preparation of ethyl5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)pyridine-2-carboxylate(Compound 275)

Ethanolic HCl was add to the compound of(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)picolinicacid (0.750 gm, 2.14 mmol) and refluxed for 7 h. The reaction mixturewas concentrated, basified with Sat. NaHCO₃, extracted with ethylacetate(2×100 mL), dried over sodium sulfate and concentrated to get crudeproduct. The crude was purified by Silica Gel (100-200) Chromatography(10% Me-OH in DCM) to get ethyl5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)picolinateas a free base. Ethanolic HCl was add to the compound of ethyl5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)picolinate(free base, 0.07 g, 0.185 mmol) and then allow to keep at for some timethen concentrated to get stick compound which was washed with ether twoto three times to get ethyl5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)picolinate.HCl Salt. (50 mg).

Example 99 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(5-methylthiophen-2-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 277)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylthiophene and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 100 Preparation of4-(3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indol-2(5H)-yl)benzenamine(Compound 278)

The title compound is prepared from a mixture of4-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)benzenamine,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 101 Preparation of2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2-phenyl-1H-pyrido[4,3-b]indole(Compound 279)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-8-methyl-2-phenyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 102 Preparation of2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2-p-tolyl-1H-pyrido[4,3-b]indole(Compound 280)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-8-methyl-2-p-tolyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 103 Preparation of2-(4-bromophenyl)-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 281)

The title compound is prepared from a mixture of2-(4-bromophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 104 Preparation of2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2-(4-nitrophenyl)-1H-pyrido[4,3-b]indole(Compound 282)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-8-methyl-2-(4-nitrophenyl)-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 105 Preparation of2-cyclobutyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 283)

The title compound is prepared from a mixture of2-cyclobutyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 106 Preparation of2,3,4,5-tetrahydro-2-(4-methoxyphenyl)-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 284)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2-(4-methoxyphenyl)-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 107 Preparation of2-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 285)

The title compound is prepared from a mixture of2-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 108 Preparation of2-(4-chlorophenyl)-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 286)

The title compound is prepared from a mixture of2-(4-chlorophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 109 Preparation of2-(4-(difluoromethyl)phenyl)-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 287)

The title compound is prepared from a mixture of2-(4-(difluoromethyl)phenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 110 Preparation of2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 288)

The title compound is prepared from a mixture of2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 111 Preparation of2,3,4,5-tetrahydro-2-(4-iodophenyl)-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 289)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2-(4-iodophenyl)-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 112 Preparation of4-(3,4-dihydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indol-2(5H)-yl)phenol(Compound 290)

The title compound is prepared from a mixture of4-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)phenol,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 113 Preparation of8-chloro-7-fluoro-2,3,4,5-tetrahydro-2-methyl-5-(2-(piperidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 292)

The title compound is prepared by following General Method 8 by using1-(bromomethyl)piperidine, 4-chloro-3-fluorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone.

Example 114 Preparation of2,8-dimethyl-5-(2-(6-methyl-1-oxidopyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole2-oxide (Compound 293)

2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(98 mg, 3.1 mmol) was stirred with hydrogen peroxide (30% in water, 0.2ml) in glacial acetic acid (1.2 ml) at 865-70° C. for 20 h to obtain 76mg of corresponding N,N′-dioxide.

Example 115 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(2,2-dimethylpiperidin-1-yl)ethanone(Compound 294)

The title compound is prepared by following Method 8 by using2-bromo-1-(2,2-dimethylpiperidin-1-yl)ethanone, 4-chlorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone.

Example 116 Preparation of2-(8-Chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(1-oxo-1,4-thiomorpholin-4-yl)-ethanone(Compound 295)

A mixture of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)aceticacid (100 mg, 0.35 mmol), Thiomorpholine-1,1-dioxide (48 mg, 0.35 mmol),DCC (81 mg, 0.39 mmol), and DMAP (48 mg, 0.39 mmol) in dry DCM (2.5 mL)was stirred at room temperature for 3 h. The reaction mixture wasfiltered through Celite and concentrated by rotary evaporation to obtain10 mg of2-(8-Chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(1-oxo-1,4-thiomorpholin-4-yl)-ethanoneas a TFA salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 117 Preparation of2-(8-Chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(1-oxo-114-thiomorpholin-4-yl)-ethanone(Compound 296)

A mixture of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)aceticacid (100 mg, 0.35 mmol), Thiomorpholine-1,1-dioxide (48 mg, 0.35 mmol),DCC (81 mg, 0.39 mmol), and DMAP (48 mg, 0.39 mmol) in dry DCM (2.5 mL)was stirred at room temperature for 3 h. The reaction mixture wasfiltered through Celite and concentrated by rotary evaporation to obtain10 mg of2-(8-Chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(1-oxo-1,4-thiomorpholin-4-yl)-ethanoneas a TFA salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 118 Preparation of1-(4-Acetyl-piperazin-1-yl)-2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanone(Compound 297)

A mixture of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)aceticacid (125 mg, 0.45 mmol) and oxalyl chloride (2 ml) in dichloromethane(6.0 ml) was stirred at 25 deg C. for 3 h. The reaction mixture wasconcentrated to dryness. The resulting crude was dissolved indichloromethane (6.0 ml) and DMAP (64 mg, 0.52 mmol) was added followedby addition of acetyl piperazine (56 mg, 0.43 mmol). The resultingmixture was stirred at 25 deg C. for 14 h. The solvent was removed invacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm,Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 20 mgof1-(4-Acetyl-piperazin-1-yl)-2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanoneas trifluoroacetic acid salt.

Example 119 Preparation of1-(3-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-one(Compound 298)

The title compound is prepared by following Method 8 by using1-(3-aminopiperidin-1-yl)-3-bromopropan-1-one, 4-methylphenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone.

Example 120 Preparation of1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidine-3-carboxylicacid (Compound 299)

The title compound is prepared by following Method 8 by using1-(3-bromopropanoyl)piperidine-3-carboxylic acid,4-methylphenylhydrazine hydrochloride, triethylamine andN-methyl-4-piperidone.

Example 121 Preparation of1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidine-4-carboxylicacid (Compound 300)

The title compound is prepared by following Method 8 by using1-(3-bromopropanoyl)piperidine-4-carboxylic acid,4-methylphenylhydrazine hydrochloride, triethylamine andN-methyl-4-piperidone.

Example 122 Preparation of5-(4-chlorophenethyl)-9-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 301)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-chlorobenzene, 3-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 123 Preparation of5-(4-chlorophenethyl)-7-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 302)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-chlorobenzene, 3-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 124 Preparation of5-(4-chlorophenethyl)-6-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 303)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-chlorobenzene, 2-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 125 Preparation of5-(4-fluorophenethyl)-9-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 304)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-fluorobenzene, 3-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 126 Preparation of5-(4-fluorophenethyl)-7-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 305)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-fluorobenzene, 3-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 127 Preparation of5-(4-fluorophenethyl)-6-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 306)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-fluorobenzene, 2-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 128 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(2-methylpyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 307)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-2-methylpyrrolidine, 4-chlorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone

Example 129 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(3-methylpyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 308)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-3-methylpyrrolidine, 4-chlorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone

Example 130 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(2,3-dimethylpyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 309)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-2,3-dimethylpyrrolidine, 4-chlorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone

Example 131 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 310)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-2,2-dimethylpyrrolidine, 4-chlorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone

Example 132 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 311)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-3,3-dimethylpyrrolidine, 4-chlorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone

Example 133 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(3-(pyrrolidin-1-yl)propyl)-1H-pyrido[4,3-b]indole(Compound 312)

The title compound is prepared by following Method 8 by using1-(3-bromopropyl)pyrrolidine, 4-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 134 Preparation of1-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)pyrrolidin-2-one(Compound 313)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)pyrrolidin-2-one, 4-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 135 Preparation of1-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)piperidin-2-one(Compound 314)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)piperidin-2-one, 4-chlorophenylhydrazine hydrochloride,triethylamine and N-methyl-4-piperidone

Example 136 Preparation of1,2-dihydro-1-hydroxy-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indol-3(5H)-one(Compound 315)

The title compound is prepared from a mixture of1,2-dihydro-1-hydroxy-2,8-dimethyl-4H-pyrido[4,3-b]indol-3(5H)-one,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 137 Preparation of3,4-dihydro-4-hydroxy-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2H-pyrido[4,3-b]indol-1(5H)-one(Compound 317)

The title compound is prepared from a mixture of3,4-dihydro-4-hydroxy-2,8-dimethyl-2H-pyrido[4,3-b]indol-1(5H)-one,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 138 Preparation of1,2-dihydro-4-hydroxy-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indol-3(5H)-one(Compound 318)

The title compound is prepared from a mixture of1,2-dihydro-4-hydroxy-2,8-dimethyl-4H-pyrido[4,3-b]indol-3(5H)-one,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 139 Preparation of3,4-dihydro-2-(hydroxymethyl)-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2H-pyrido[4,3-b]indol-1(5H)-one(Compound 319)

The title compound is prepared from a mixture of3,4-dihydro-2-(hydroxymethyl)-8-methyl-2H-pyrido[4,3-b]indol-1(5H)-one,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 140 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(2-methylpiperidin-1-yl)ethanone(Compound 321)

A mixture of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)aceticacid (125 mg, 0.45 mmol) and oxalyl chloride (2 ml) in dichloromethane(6.0 ml) was stirred at 25 deg C. for 3 h. After completion of thereaction (monitored by TLC), the reaction mixture was concentrated todryness. To the resulting crude dichloromethane (6.0 ml) and DMAP (64mg, 0.52 mmol) was added followed by addition of 2-methylpiperidine (43mg, 0.43 mmol). The resulting mixture was stirred at 25 deg C. for 14 h.After completion of the reaction (monitored by LCMS), solvent wasremoved in vacuo and purified by reverse-phase chromatography (C-18, 500mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL)to obtain 30 mg of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(2-methylpiperidin-1-yl)ethanoneas trifluoroacetic acid salt.

Example 141 Preparation of2,8-dimethyl-5-(2-(5-methylpyrazin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 322)

To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (0.75 mL) was added powderedpotassium hydroxide (0.281 g, 5.0 mmol) and allowed to stir for 10 minat RT. 2-methyl-5-vinyl pyrazine (0.151 g, 1.2 mmol) was added andstirred for further 2 h. at 60 deg C. After completion (TLC), reactionmixture was diluted with water (25 mL) and extracted with ethyl acetate(3×100 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure. The crude was purified throughcolumn chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) to provide the desiredcompound as yellow oil (0.05 g, 31% yield).2,8-Dimethyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.05 g, 0.156 mmol) was dissolved in THF (2.0 mL). A solution of oxalicacid dihydrate (0.015 g, 0.000119 mol) in THF (1.0 mL) was added andstirred for 30 min at RT. Precipitate obtained was filtered and dried togive oxalate salt as white solid (0.03 g, 47% yield).

Example 142 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(2-methylpyrimidin-5-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 323)

To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g, 0.0005 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.14 g, 0.0025 mol) and allowed to stir r for 10min at RT. 2-methyl-5-vinyl pyrimidine (0.151 g, 0.0012 mol) was addedand stirred for further 3 h at 80 deg C. After completion (TLC),reaction mixture was diluted with water (15 mL) and extracted with ethylacetate (3×50 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through column chromatography (7%MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height ofsilica—approx. 5 inch) then purified through preparative TLC. to get thedesired compound as yellow oil (0.025 g, 16% yield).2,8-Dimethyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrid[4,3-b]indole(0.025 g, 0.000078 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.0098 g, 0.000078 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.015 g, 47% yield).

Example 143 Preparation of8-chloro-5-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 324)

To a suspension of sodium hydride (0.014 g, 0.00054 mol) in dry DMF (3mL), 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g,0.00045 mol) was added at ice cold temp and stirred for 2 h at roomtemperature. Reaction mix was cooled to −20° c. and5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.183 g, 0.00068 mol) wasadded, stirred for 1 h at 15° c., Reaction was monitor by TLC. Aftercompletion (TLC), reaction mix was cooled to 0° C. and water (10 mL) wasadded, extracted with ethyl acetate (3×100 mL). The organic layer wasdried over anhydrous sodium sulphate and concentrated under reducedpressure using rotary evaporator. The crude was purified through columnchromatography (4% Methanol:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) to provide desiredcompound as brown oil (0.06 g, 32% yield).8-Chloro-2-methyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.06 g, 0.000147 mol) was dissolved in THF (1.0 mL), A solution ofoxalic acid dihydrate (0.016 g, 0.000126 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as off white solid (0.050 g, 68% yield).

Example 144 Preparation of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)propan-1-one(Compound 325)

A mixture of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoicacid (50 mg, 0.17 mmol), 4-methyl Piperidine (0.02 mL, 0.17 mmol), DCC(38 mg, 0.18 mmol), and DMAP (23 mg, 0.18 mmol) in dry DCM (2 mL) wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough Celite and concentrated to obtain 12 mg of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)propan-1-oneas TFA salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 145 Preparation of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)propan-1-one(Compound 326)

3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoicacid (0.1 g, 0.34 mmol) was taken in dichloromethane (3 mL) and wascooled to 0 deg C. Oxalyl chloride (0.04 mL, 0.41 mmol) was addeddrop-wise to the reaction mixture. A catalytic amount (1 drop) ofdimethyl formamide was added to the reaction mixture. Reaction mixturewas stirred for 1 h at room temperature. Excess oxalyl chloride wasdistilled away under reduced pressure. To this residue, a solution ofPiperidine (0.036 mL, 0.374 mmol) in 2 mL DCM and DMAP (0.055 g, 0.45mmol) was added under nitrogen at room temperature and reaction mass wasstirred for 30 min at room temperature. Reaction mixture was quenchedwith water and neutralized with 10% NaHCO3, extracted with Ethyl acetate(10 ml×2). Combined organic layers dried over sodium sulphate andconcentrated under reduced pressure to obtain crude product which wasfurther purified by flash column chromatography using Methanol:DCM(5:95) to afford 12 mg of product. This product was stirred in THF (2mL) and oxalic acid (9 mg, 0.06 mmol) for 15 min and mixture wasconcentrated under vacuo to afford 11 mg of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)propan-1-oneas oxalate Salt.

Example 146 Preparation of5-(4-chlorophenethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylicacid (Compound 327)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-chlorobenzene, methyl 4-hydrazinobenzoate,triethylamine and N-methyl-4-piperidone

Example 147 Preparation of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-morpholinopropan-1-one(Compound 328)

A mixture of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoicacid (100 mg, 0.34 mmol), morpholine (29 mg, 0.34 mmol), DCC (77 mg,0.37 mmol), and DMAP (46 mg, 0.37 mmol) in dry DCM (2.5 mL) was stirredat room temperature for 3 h. The reaction mixture was filtered throughCelite and concentrated by rota vapor to obtain 10 mg of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-morpholinopropan-1-oneas TFA salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 148 Preparation of2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 329)

2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol),2-vinylpyridine (0.26 mg, 2.5 mmol), sodium (5 mg, 0.21 mmol) and CuSO4(5 mg, catalytic) in ethanol (4 mL) was at 120° C. for 16 h to obtain 60mg of2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt after purification on reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

Example 149 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-morpholinoethanone(Compound 330)

To a solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl) acetic acid(100 mg, 0.38 mmol) in DCM (10 ml) was added DCC (95 mg, 0.46 mmol),DMAP (56 mg, 0.46 mmol), and stirred for 5 min at RT, morpholine (1 ml,11.5 mmol) was added and stirred at 25 deg C. for 14 h. The reactionmixture was concentrated to dryness and The resulting crude was purifiedby reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL) to obtain 10 mg (Yield 5.8%) of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-morpholinoethanone as TFA salt.

Example 150 Preparation of5-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 331)

To a suspension of DMF (5 mL) and sodium hydride (0.024 g, 0.0006 mol)at 0° c., 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g,0.0005 mol) was added and stirred for 2 h at room temperature, Reactionmix was cooled to −20° c. and5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.2 g, 0.00075 mol) wasadded, stirred for 1 h at 15° C. After completion (TLC), reaction masswas cooled to 0° c. and water (10 mL) was added, and extracted withethyl acetate (3×100 mL). The organic layer was dried over anhydroussodium sulphate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through column chromatography (3-4%methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Heightof silica—approx. 5 inch) to provide desired compound as brown oil (0.04g, 20% yield).2,8-Dimethyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.04 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.012 g, 0.0000952 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as off white solid (0.030 g, 61% yield).

Example 151 Preparation of2,3,4,5-tetrahydro-2-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole(Compound 332)

A solution of 2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (186mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324 mg, 2.3 mmol) and60% NaH (120 mg, 3 mmol) in DMF (3 ml) were heated at 120° C. for 16 hto obtain 30 mg of2,3,4,5-tetrahydro-2-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indoleafter purification by silica gel chromatography (230-400 mesh) usingmethanol-dichloromethane gradient.

Example 152 Preparation of5-[2-(4-Ethoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 333)

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001mol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powdered potassiumhydroxide (0.448 g, 0.008 mol) was added and heated at 120° C. for 2 h.1-(2-Bromo-ethyl)-4-ethoxy-benzene (0.228 g, 0.001 mol) was added at thesame temperature and stir for 3 h. at RT (TLC showed incompletereaction). Reaction mixture was diluted with water (30 mL) and extractedwith ethyl acetate (3×100 mL). Organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through column chromatography (4%MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height ofsilica—approx. 5 inch) to provide the desired compound as light yellowoil (0.035 g, 10% yield).5-[2-(4-Ethoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.035 g, 0.0001 mol) was dissolved in THF (0.5 mL), A solution ofoxalic acid dihydrate (0.013 g, 0.0001 mol) in THF (0.5 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as off white solid (0.015 g, 34% yield).

Example 153 Preparation of5-[2-(4-Ethoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 334)

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001mol) was dissolved in N-methyl 2-pyrolidone (3.0 mL), powdered potassiumhydroxide (0.448 g, 0.008 mol) was added and heated at 120° C. for 2 h.1-(2-Bromo-ethyl)-4-ethoxy-benzene (0.228 g, 0.001 mol) was added at thesame temperature and stir for 3 h. at RT (TLC showed incompletereaction). Reaction mixture was diluted with water (30 mL) and extractedwith ethyl acetate (3×100 mL). Organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through column chromatography (4%MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height ofsilica—approx. 5 inch) to provide the desired compound as light yellowoil (0.035 g, 10% yield).5-[2-(4-Ethoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.035 g, 0.0001 mol) was dissolved in THF (0.5 mL), A solution ofoxalic acid dihydrate (0.013 g, 0.0001 mol) in THF (0.5 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as off white solid (0.015 g, 34% yield).

Example 154 Preparation of5-(4-tert-butoxyphenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 335)

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001mol) was dissolved in N-methyl 2-pyrolidone (2.0 mL). Powdered potassiumhydroxide (0.5 g, 0.0089 mol) was added and heated at 100° C. for 3 h.Reaction mass was cooled to RT and1-(2-Bromo-ethyl)-4-tert-butoxy-benzene (0.245 g, 0.001 mol) was addedat the same temperature and stir for 2 h at RT (TLC showed incompletereaction). Reaction mixture was diluted with water (50 mL) and extractedwith ethyl acetate (2×100 mL). Organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through column chromatography (0.5%MeOH:DCM in neutral alumina, Diameter of column—2.5 cm, Height ofalumina—approx. 5 inch) then further purified by preparative TLC toprovide the desired compound as light yellow oil (0.024 g, 6% yield).5-[2-(4-tert-Butoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.024 g, 0.000063 mol) was dissolved in THF (1.0 mL), A solution ofoxalic acid dihydrate (0.008 g, 0.000063 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as off white solid (0.020 g, 67% yield).

Example 155 Preparation of8-Chloro-5-[2-(4-methoxy-phenyl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1Hpyrido[4,3-b]indole (Compound 336)

8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.22 g,0.001 mol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powderedpotassium hydroxide (0.224 g, 0.004 mol) was added and heated at 100 degC. for 3 h. 1-(2-Bromo-ethyl)-4-methoxy-benzene (0.214 g, 0.001 mol) wasadded at the same temperature and stir for 6 h. at RT. Reaction mixturewas diluted with water (30 mL) and extracted with ethyl acetate (3×50mL). Organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure using rotary evaporator. The crudewas purified through column chromatography (4% MeOH:DCM in silica100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5inch) to provide the desired compound as light yellow oil (0.02 g, 6%yield).8-Chloro-5-[2-(4-methoxy-phenyl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.020 g, 0.0564 mol) was dissolved in THF (1.0 mL), A solution ofoxalic acid dihydrate (0.007 g, 0.0564 mol) in 1.5 mL THF was added andstirred for 30 min at RT. The precipitate was filtered and dried to giveoxalate salt as white solid (0.01 g, 40% yield).

Example 156 Preparation of5-(3-fluoro-4-methoxyphenethyl)-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 337)

8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g,0.0022 mol) was dissolved in N-methyl 2-pyrolidone (4.0 mL). Powderedpotassium hydroxide (1 g, 0.008 mol) was added and heated at 100° C. for2 h. 4-(2-Bromo-ethyl)-2-fluoro-1-methoxy-benzene (0.520 g, 0.0022 mol)was added at the room temperature and stir for 0.5 h at RT (TLC showedincomplete reaction). Reaction mixture was diluted with water (200 mL)and extracted with ethyl acetate (3×100 mL). Organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressureusing rotary evaporator. The crude was purified through columnchromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) to provide the desiredcompound as light yellow oil (0.038 g, 4% yield).8-Chloro-5-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.038 g, 0.00010 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.012 g, 0.00010 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as off white solid (0.016 g, 34% yield).

Example 157 Preparation of 8-chloro-6-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 338)

To a solution of8-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(300 mg, 1.26 mmol) in NMP (3.0 ml), powdered KOH (705 mg, 12.57 mmol)was added and stirred for 10 min at 25 deg C. After which2-(trifluoromethyl)-5-vinylpyridine (435 mg, 2.5 mmol) was added slowlyto the above solution and stirred for 24 h at 25 deg C. After completionof the reaction (monitored by LCMS), DM water was added to the crude andextracted with the ethylacetate. The organic layer was separated, driedand concentrated. The resulting crude was purified by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL) to obtain 15 mg of8-chloro-6-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indoleas TFA salt.

Example 158 Preparation of6,8-dichloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 339)

The title compound is prepared from a mixture of6,8-dichloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 159 Preparation of7,9-difluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 340)

The title compound is prepared from a mixture of7,9-difluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 160 Preparation of5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-8-(trifluoromethoxy)-1H-pyrido[4,3-b]indole(Compound 341)

To a solution of5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-8-(trifluoromethoxy)-1H-pyrido[4,3-b]indole(200 mg, 0.74 mmol) in NMP (1.5 ml), powdered KOH (415 mg 7.4 mmol) wasadded and stirred for 10 min at 25 deg C. after which2-(trifluoromethyl)-5-vinylpyridine (256 mg, 1.48 mmol) was added slowlyto the above solution and stirred at 25 deg C. for 2 h. After completionof the reaction (monitored by LCMS), DM water was added to the crude andextracted with the ethyl acetate. The organic layer was dried andconcentrated. The resulting crude was purified by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL) to obtain 50 mg (Yield 15.24%) of5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-8-(trifluoromethoxy)-1H-pyrido[4,3-b]indoleas TFA salt.

Example 161 Preparation of8-Isopropyl-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 342)

To a solution of8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g,0.43 mmol) in N-methyl 2-pyrolidone (0.5 mL) was added powderedpotassium hydroxide (0.096 g, 1.72 mmol) and allowed to stir for 10 minat RT. 2-trifluoromethyl-5-vinyl pyridine (0.19 g, 1.1 mmol) was addedand stirred for further at 35 deg C. for 3 h. Reaction mixture wasdiluted with brine (5 mL) and extracted with ethyl acetate (3×50 mL).The organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude was purified throughcolumn chromatography (5% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) to provide the desiredcompound as brown oil (0.17 g, 45% yield).Isopropyl-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.080 g, 0.19 mmol) was dissolved in THF (2.0 mL). A solution of oxalicacid dihydrate (0.017 g, 0.19 mmol) in THF (2 mL) was added and stirredfor 30 min at RT, Precipitate obtained was filtered and dried to giveoxalate salt as white solid (0.045 g, 46% yield).

Example 162 Preparation ofChloro-7-fluoro-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 343)

To a solution of8-Chloro-7-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g. 0.0041 mol) in N-methyl 2-pyrolidone (0.5 mL) was added powderedpotassium hydroxide (0.08 g, 0.00143 mol) and allowed to stir for 10 minat RT. 2-trifluoromethyl-5-vinyl pyridine (0.079 g, 0.00046 mol) wasadded and stirred for further 15 h. at rt, After completion (TLC),reaction mixture was diluted with water (5 mL) and extracted with ethylacetate (3×50 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through preparative HPLC to give thedesired compound 10 as light yellow solid (0.02 g, 12% yield).8-Chloro-7-fluoro-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.02 g, 0.0000485 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.006 g, 0.0000485 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as white solid (0.015 g, 62% yield).

Example 163 Preparation of8-chloro-9-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 344)

The title compound is prepared from a mixture of8-chloro-9-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 164 Preparation of7-aza-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 345)

The title compound is prepared from a mixture of9-aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 165 Preparation of9-aza-2-methyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 346)

The title compound is prepared from a mixture of9-aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 166 Preparation of8-aza-2-methyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 347)

The title compound is prepared from a mixture of8-aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 167 Preparation of6,8-diaza-2-methyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 348)

The title compound is prepared from a mixture of6,8-diaza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 168 Preparation of8-Chloro-2-methyl-5-(2-pyrrol-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 349)

8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.45mmol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powderedpotassium hydroxide (0.224 g, 4 mmol) was added and heated at 100 deg C.for 3 h. 2-(2-Bromo-ethyl)pyridine (0.09 g, 0.51 mol) was added at thesame temperature and stir for 3 h at RT Reaction mixture was dilutedwith water (30 mL) and extracted with ethyl acetate (3×50 mL). Organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure using rotary evaporator. The crude was purified throughcolumn chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) to provide the desiredcompound as light yellow oil (0.01 g, 7% yield).8-Chloro-2-methyl-5-(2-pyrrol-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.010 g, 0.0319 mmol) was dissolved in THF (0.5 mL), A solution ofoxalic acid dihydrate (0.004 g, 0.0319 mol) in THF (0.5 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as white solid (0.01 g, 78% yield).

Example 169 Preparation of8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1,2-dimethyl-1H-pyrido[4,3-b]indole(Compound 350)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-1,2-dimethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 170 Preparation of3-(8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol(Compound 351)

3-(8-chloro-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanol(300 mg, 1.03 mmol), 2-trifluoromethyl-5-vinylpyridine (140 mg, 0.809mmol) and potassium hydroxide (310 mg, 5.5 mmol) in 0.6 ml of NMP washeated to 60 deg C. for 2 h. The reaction mass was cooled at RT anddiluted with 20 ml of ethyl acetate. The organic layer was washed withbrine and dried over sodium sulphate and concentrated under vacuum. Itwas purified on 230-400 silica gel (flash) deactivated withtriethylamine using ethyl acetate/methanol (5-10%) as eluant, followedby isolation of3-(8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)cyclopentanolby PREP HPLC. Yield: 70 mg as TFA salt.

Example 171 Preparation of8-chloro-4-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 352)

The title compound is prepared from a mixture of8-chloro-4-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 172 Preparation of9-aza-2,8-dimethyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 353)

Carboline (150 mg, 0.746 mmol, 1 equiv),2-trifluoromethyl-5-vinylpyridine (142 mg, 0.82 mmol, 1.1 equiv) and KOH(146 mg, 2.61 mmol, 3.5 equiv) were stirred with 0.45 ml of NMP at 50°C. for 3.5 h. Reaction mixture was then diluted with ethyl acetate (15ml) and washed with brine. Organic part was evaporated under vacuum andcolumn purified over neutral alumina using a gradient of ethylacetate/MeOH (0-100%). Preparative HPLC was used to further purify thefraction containing the desired mass by LC-MS. Yield: 35 mg as TFA Salt.

Example 173 Preparation of8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,3-dimethyl-1H-pyrido[4,3-b]indole(Compound 354)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2,3-dimethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 174 Preparation of6-aza-2,8-dimethyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 355)

The title compound is prepared from a mixture of6-aza-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 175 Preparation of7-aza-2,8-dimethyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 356)

The title compound is prepared from a mixture of7-aza-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 176 Preparation of8-Ethyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 357)

To a solution of8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.107 g, 0.5mmol) in N-methyl 2-pyrolidone (2 mL) was added powdered potassiumhydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT.2-methyl-5-vinyl pyridine (0.065 g, 0.55 mmol) was added and stirred forfurther 24 h. at 120 deg C., After completion of TLC, Reaction mixturewas diluted with water (30 mL) and extracted with ethyl acetate (3×50mL). The organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude was purified throughcolumn chromatography (8% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) to provide the desiredcompound as brown oil (0.034 g, 20% yield).8-Ethyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.034 g, 0.102 mmol) was dissolved in THF (0.5 mL). A solution ofoxalic acid dihydrate (0.013 g, 0.102 mol) in THF (0.5 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as off white solid (0.015 g, 32% yield).

Example 177 Preparation of8-Ethyl-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 358)

To a solution of8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.107 g.0.0005 mol) in N-methyl 2-pyrolidone (2.0 mL) was added powderedpotassium hydroxide (0.224 g, 0.004 mol) and allowed to stir for 10 minat RT. 2-trifluoromethyl-5-vinyl pyridine (0.095 g, 0.00055 mol) wasadded and stirred for further 1 h. at 60 deg C., After completion ofTLC, Reaction mixture was diluted with brine (5 mL) and extracted withethyl acetate (3×50 mL). The organic layer was dried over anhydroussodium sulphate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through column chromatography (4%MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height ofsilica—approx. 5 inch) to provide the desired compound as brown oil(0.11 g, 57% yield).8-Ethyl-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g, 0.000258 mol) was dissolved in THF (2.0 mL). A solution ofoxalic acid dihydrate (0.032 g, 0.000258 mol) in THF (2 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as white solid (0.080 g, 65% yield).

Example 178 Preparation of5-[2-(6-Ethyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 359)

To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.15 g. 0.749 mmol) in N-methyl 2-pyrolidone (1.2 mL) was addedpowdered potassium hydroxide (0.42 g, 7.49 mmol) and allowed to stir for10 min at RT. 2-Ethyl-5-vinyl-pyridine (0.299 g, 2.24 mmol) was addedand stirred for further 18 h. at 100 deg C. After completion (TLC),reaction mixture was diluted with water (15 mL) and extracted with ethylacetate (3×50 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure. The crude was purifiedthrough column chromatography (7% MeOH:DCM in silica 100-200 mesh,Diameter of column 2.5 cm, Height of silica—approx. 5 inch), Thenfurther purified by preparative TLC, to give the desired compound asyellow oil (0.045 g, 18% yield).5-[2-(6-Ethyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.040 g, 0.12 mol) was dissolved in THF (1.0 mL). A solution of oxalicacid dihydrate (0.012 g, 0.096 mol) in THF (1.0 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as off white solid (0.030 g, 60% yield).

Example 179 Preparation of5-[2-(6-Isopropyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 360)

To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g. 0.5 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.140 g, 2.5 mmol) and allowed to stir for 10 minat RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 1.25 mol) was added andstirred for further 4 h at 100 deg C. After completion (TLC), reactionmixture was diluted with water (15 mL) and extracted with ethyl acetate(3×50 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure. The crude was purified throughcolumn chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch), Then further purifiedby preparative TLC, to give the desired compound as yellow oil (0.025 g,14% yield).5-[2-(6-Isopropyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.025 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.0095 g, 0.00007 mol) in THF (0.5 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.024 g, 77% yield).

Example 180 Preparation of8-Chloro-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 361)

To a solution of8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.075 g,0.34 mmol) in N-methyl 2-pyrolidone (0.5 mL) was added powderedpotassium hydroxide (0.095 g, 1.7 mmol) and allowed to stir for 10 minat RT. 2-methyl-5-vinyl pyrimidine (0.102 g, 0.85 mmol) was added andstirred for further at 80 deg C. 3 h. After completion (TLC), reactionmixture was diluted with water (15 mL) and extracted with ethyl acetate(3×50 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure. The crude was purified throughcolumn chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) then purified throughpreparative TLC to get the desired compound as yellow oil (0.020 g, 13%yield).8-Chloro-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.020 g, 0.06 mmol) was dissolved in THF (1.0 mL). A solution of oxalicacid dihydrate (0.008 g, 0.06 mmol) in THF (0.5 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as off white solid (0.008 g, 32% yield).

Example 181 Preparation of8-Ethyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 362)

To a solution of8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g.0.00046 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.13 g, 0.0023 mol) and allowed to stir for 10 minat RT. 2-methyl-5-vinyl pyrimidine (0.14 g, 0.00116 mol) was added andstirred for further 3 h. At 80 deg C. After completion (TLC), reactionmixture was diluted with water (15 mL) and extracted with ethyl acetate(3×50 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure using rotary evaporator. Thecrude was purified through column chromatography (7% MeOH:DCM in silica100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5inch) then purified through preparative TLC. to get the desired compoundas yellow oil (0.032 g, 20% yield).8-Ethyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.032 g, 0.000095 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.012 g, 0.000095 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.030 g, 75% yield).

Example 182 Preparation of8-Chloro-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 363)

To a solution of8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.11 g, 5.0mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassiumhydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT.2-methyl-5-vinyl pyrazine (0.065 g, 0.55 mmol) was added and stirred forfurther 2 h at 60 deg C. After completion (TLC), reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (3×100 mL).The organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude was purified throughcolumn chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch) to provide the desiredcompound as yellow oil (0.09 g, 54% yield).8-Chloro-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.09 g, 0.26 mmol) was dissolved in THF (1.0 mL). A solution of oxalicacid dihydrate (0.034 g, 0.26 mmol) in THF (1.0 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as white solid (0.08 g, 68% yield).

Example 183 Preparation of8-Ethyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 364)

To a solution of8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.054 g.0.25 mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powderedpotassium hydroxide (0.112 g, 0.002 mol) and allowed to stir for 10 minat RT. 2-methyl-5-vinyl pyrazine (0.033 g, 0.75 mmol) was added andstirred for further 1 h. at 60 deg C. After completion (TLC), reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×50 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure using rotary evaporator. Thecrude was purified through column chromatography (7% MeOH:DCM in silica100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5inch) to provide the desired compound as yellow oil (0.05 g, 60% yield).8-Ethyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.05 g, 0.000149 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.019 g, 0.000149 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.035 g, 50% yield).

Example 184 Preparation of8-chloro-5-(2-(4-(trifluoromethyl)-6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 365)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 185 Preparation of8-ethyl-5-(2-(4-(trifluoromethyl)-6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 366)

The title compound is prepared from a mixture of8-ethyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 186 Preparation of5-(2-(4-(trifluoromethyl)-6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 367)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 187 Preparation of5-(2-(4-(trifluoromethyl)-6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole(Compound 368)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 188 Preparation of8-Isopropyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 369)

To a solution of8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g.0.87 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.5 g, 8.7 mmol) and allowed to stir for 10 min atRT. 2-methyl-5-vinyl pyrazine (0.25 g, 2.1 mmol) was added and stirredfor further 5 h. at 60 deg C. After completion (TLC), reaction mixturewas diluted with water (20 mL) and extracted with ethyl acetate (3×100mL). The organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure using rotary evaporator. The crudewas purified through column chromatography (6% MeOH:DCM in silica100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5inch) then further purified through preparative TLC to provide thedesired compound as yellow solid (0.05 g, 16% yield).8-Isopropyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.05 g, 0.143 mmol) was dissolved in THF (2.0 mL). A solution of oxalicacid dihydrate (0.018 g, 0.143 mmol) in THF (1.0 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as off white solid (0.02 g, 32% yield).

Example 189 Preparation of8-Isopropyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 370)

To a solution of8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g.0.000438 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.122 g, 0.00021 mol) and allowed to stir for 10min at RT. 2-methyl-5-vinyl pyrimidine (0.13 g, 0.00109 mol) was addedand stirred for further 3 h. At 80 deg C. After completion (TLC),reaction mixture was diluted with water (15 mL) and extracted with ethylacetate (3×50 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure using rotaryevaporator. The crude was purified through column chromatography (7%MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height ofsilica—approx. 5 inch) then purified through preparative TLC. To get thedesired compound as yellow oil (0.036 g, 24% yield).8-Isopropyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole0.036 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.013 g, 0.000103 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.022 g, 49% yield).

Example 190 Preparation of8-Chloro-5-[2-(6-ethyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 371)

To a solution of8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g,0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.4 g, 6.8 mmol) and allowed to stir for 10 min atRT. 2-Ethyl-5-vinyl-pyridine (0.28 g, 2.04 mmol) was added and stirredfor further at 100 deg C. for 18 h. After completion (TLC), reactionmixture was diluted with water (15 mL) and extracted with ethyl acetate(3×100 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure. The crude was purified throughcolumn chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch), Then further purifiedby preparative TLC, to give the desired compound as yellow oil (0.025 g,10% yield).8-Chloro-5-[2-(6-ethyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.025 g, 0.07 mmol) was dissolved in THF (1.0 mL). A solution of oxalicacid dihydrate (0.009 g, 0.07 mmol) in THF (1.0 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as off white solid (0.010 g, 32% yield).

Example 191 Preparation of8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 372)

To a solution of8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g.0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.140 g, 0.0025 mol) and allowed to stir for 10 minat RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 0.00125 mol) was added andstirred for further 4 h. at 100 deg C. After completion (TLC), reactionmixture was diluted with water (15 mL) and extracted with ethyl acetate(3×50 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure using rotary evaporator. Thecrude was purified through column chromatography (7% MeOH:DCM in silica100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5inch), Then further purified by preparative TLC, to give the desiredcompound as yellow oil (0.027 g, 15% yield).8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.027 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.009 g, 0.00007 mol) in THF (0.5 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.027 g, 81% yield).

Example 192 Preparation of8-chloro-5-(2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 373)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 193 Preparation of8-chloro-5-(2-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 374)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 194 Preparation of2′,8′-dimethyl-5′-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole](Compound 375)

The title compound is prepared from a mixture of2′,8′-dimethyl-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole],2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 195 Preparation of2′,8′-dimethyl-5′-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole](Compound 376)

The title compound is prepared from a mixture of2′,8′-dimethyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole],2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 196 Preparation of5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,3,3,8-tetramethyl-1H-pyrido[4,3-b]indole(Compound 377)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,3,3,8-tetramethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 197 Preparation of5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1,1,2,8-tetramethyl-1H-pyrido[4,3-b]indole(Compound 378)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-1,1,2,8-tetramethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 198 Preparation of2,3,4,5-tetrahydro-2,6-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 379)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 199 Preparation of5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole(Compound 380)

To a solution of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole(200 mg, 1.0 mmol) in NMP (2.5 ml), powdered KOH (561 mg, 10 mmol) wasadded and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added slowly to theabove solution and stirred for 16 h at 25 deg C. After completion of thereaction (monitored by LCMS), water (5 mL) was added to the crude andextracted with the ethyl acetate. The organic layer was dried andconcentrated. The resulting crude was purified by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL) to obtain 40 mg (8.2%) of5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indoleas TFA salt.

Example 200 Preparation of3-(6-(trifluoromethyl)pyridin-3-yl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoicacid (Compound 381)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,(Z)-3-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid and KOH (5-7 equiv)in NMP at a temperature ranging between 25 deg C. to 100 deg C. Theproduct obtained is isolated by preparative HPLC.

Example 201 Preparation of ethyl3-(6-(trifluoromethyl)pyridin-3-yl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate(Compound 382)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, (Z)-ethyl3-(6-(trifluoromethyl)pyridin-3-yl)acrylate and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 202 Preparation of2-(6-(trifluoromethyl)pyridin-3-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoicacid (Compound 383)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid and KOH (5-7 equiv) inNMP at a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 203 Preparation of methyl2-(6-(trifluoromethyl)pyridin-3-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate(Compound 384)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, methyl2-(6-(trifluoromethyl)pyridin-3-yl)acrylate and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 204 Preparation of5-(2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 385)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 205 Preparation of5-(2-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 386)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyrazine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 206 Preparation of2,8-Dimethyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 387)

To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g. 0.49 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min atRT. 5-vinyl pyrimidine (0.132 g, 1.25 mmol) was added and stirred forfurther 5 h at 60 deg C. After completion (TLC), reaction mixture wasdiluted with water (15 mL) and extracted with ethyl acetate (3×50 mL).The organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude was purified throughcolumn chromatograph y (7% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica approx. 5 inch), Then further purifiedby preparative TLC, to give the desired compound as yellow oil (0.050 g,32.6% yield).2,8-Dimethyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.040 g, 0.13 mol) was dissolved in THF (1.0 mL). A solution of oxalicacid dihydrate (0.015 g, 0.119 mol) in THF (1.0 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as off white solid (0.046 g, 90% yield).

Example 207 Preparation of8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,3,3-trimethyl-1H-pyrido[4,3-b]indole(Compound 388)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2,3,3-trimethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 208 Preparation of8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1,1,2-trimethyl-1H-pyrido[4,3-b]indole(Compound 389)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-1,1,2-trimethyl-1H-pyrido[4,3-b]indole,2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 209 Preparation of8′-chloro-2′-methyl-5′-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole](Compound 390)

The title compound is prepared from a mixture of8′-chloro-2′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole],2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 210 Preparation of8′-chloro-2′-methyl-5′-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole](Compound 391)

The title compound is prepared from a mixture of8′-chloro-2′-methyl-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole],2-(trifluoromethyl)-5-vinylpyridineand KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to100 deg C. The product obtained is isolated by preparative HPLC.

Example 211 Preparation of8-Isopropyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 392)

To a solution of8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g,0.877 mmol) in N-methyl 2-pyrolidone (2 mL) was added powdered potassiumhydroxide (0.2 g, 3.5 mmol) and allowed to stir for 10 min at RT.2-methyl-5-vinyl pyridine (0.104 g, 0.877 mmol) was added and stirredfor further at 120 deg C. for 20 h. Reaction mixture was diluted withwater (30 mL) and extracted with ethyl acetate (3×50 mL). The organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure. The crude was purified through column chromatography(5% Me OH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Heightof silica—approx. 5 inch) and further purified with preparative TLC toprovide the desired compound as brown oil (0.045 g, 15% yield).8-Isopropyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.045 g, 0.129 mmol) was dissolved in THF (2.0 mL). A solution ofoxalic acid dihydrate (0.016 g, 0.129 mmol) in THF (2 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as off white solid (0.045 g, 80% yield).

Example 212 Preparation of tert-butyl1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate(Compound 393)

3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid(500 mg, 1.8 mmol) was stirred with tert-butyl piperidin-4-ylcarbamate(0.366 ml, 1.8 mmol), EDCI-HCl (0.35 g, 1.8 mmol) and triethyl amine(0.253 ml, 1.8 mmol) in dichloromethane (20 ml) to obtain 50 mg oftert-butyl1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate as a trifluoroacetate salt after purification on neutralalumina chromatography eluting with methanol-dichloromethane gradientfollowed by reverse-phase chromatography (C-18, 500 mm×50 mm, MobilePhase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% Bto 80% B in 30 min, injection vol. 5 mL).

Example 213 Preparation of5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)-2-methylpyridine1-oxide (Compound 394)

To the N,N′-dioxide intermediate (76 mg, 0.21 mmol) in acetic acid (0.3ml) and methanol (2 ml) sodium bisulphite (40% in water, 0.2 ml) wasadded and the reaction mixture was stirred at 0 deg C. for 0.5 h. Thereaction mixture was basified with saturated aqueous NaHCO₃ andextracted with ethyl acetate to obtain 50 mg of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indoleN′-oxide.

Example 214 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)ethanone(Compound 395)

2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl) acetic acid(1.5 g, 5.8 mmol) was taken in dichloromethane (15 mL) and was cooled to0° C. using an ice-bath; oxalyl chloride (0.61 mL, 6.9 mmol) was addeddrop-wise, catalytic amount (2 drop) of dimethyl formamide was added tothe reaction mixture. After the addition, reaction mixture was stirredfor 1 h at room temperature. Excess oxalyl chloride was distilled awayunder reduced pressure. To this residue, solution of Piperidine (0.68mL, 6.9 mmol) in 4 mL DCM and DMAP (0.71 g, 5.8 mmol) was added undernitrogen at room temperature and reaction mass was stirred for 0.5 h atroom temperature. The reaction mixture was quenched by ice water andextracted with Dichloromethane and purified by column chromatography togives 0.8 g of desired compound as free base. The free base wasconverted into HCl salt by treatment with ethanolic HCl. Sodium hydride(0.8 g, 20 mmol) washed with hexane for removal of oil and dried undervacuum. Then sodium hydride was taken in THF. To this solution2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) inTHF was added drop wise at 0° C. Then reaction mixture stirred for 0.5h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.9 g, 12 mmol)in THF was added drop wise in react ion mixture. Then reaction mixturestirred at RT for 2 h. Reaction monitored by TLC. After completion ofreaction, reaction mixture quench with ice-water. THF was evaporated andaqueous layer was extracted with ethyl acetate. Organic layer was driedover anhydrous sodium sulphate. The crude compound was washed withhexane and diethyl ether for removal of color impurities thenrecrystallized by using methanol to give 1 g of desired compound then itwas stirred with ethanolic HCl to give HCl salt of2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.

Example 215 Preparation of8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 396)

To a solution of8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg,0.82 mmol) in NMP (3.0 ml), powdered KOH (462 mg, 8.23 mmol) was addedand stirred for 10 min at 25 deg C. After which2-(trifluoromethyl)-5-vinylpyridine (286 mg, 1.65 mmol) was added slowlyto the above solution and stirred for 14 h at 25 deg C. After completionof the reaction (monitored by LCMS), water (5 mL) was added to the crudeand extracted with the ethylacetate. The organic layer was dried andconcentrated. The resulting crude was purified by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, gradient: 10% B to 80% B in 30 min,injection vol. 5 mL) to obtain 30 mg of8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indoleas TFA salt

Example 216 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(isoindolin-2-yl)ethanone(Compound 397)

A mixture of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid(50 mg, 0.205 mmol), Isoindoline (23 mg, 0.205 mmol), DCC (46 mg, 0.22mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred atroom temperature for 3 h. The reaction mixture was filtered throughCelite and concentrated using rotary evaporator afforded 16.3 mg of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(isoindolin-2-yl)ethanoneas TFA Salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 217 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethanone(Compound 398)

A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 1,2,3,4 Tetrahydroisoquinoline (25 mg,0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dryDCM (2.0 mL) was stirred at room temperature for 3 h. The reactionmixture was filtered through Celite and concentrated using rotaryevaporator afforded 7.9 mg of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethanoneas TFA Salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 218 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-thiomorpholinoethanone(Compound 399)

A mixture of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid(50 mg, 0.205 mmol), Thiomorpholine (19 mg, 0.205 mmol), DCC (46 mg,0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirredat room temperature for 3 h. The reaction mixture was filtered throughCelite and concentrated using rotary evaporator afforded 34.2 mg of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-thiomorpholinoethanoneas TFA Salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 219 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethanone(Compound 400)

The title compound is prepared by following Method 8 by using2-bromo-1-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethanone,(2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole),triethylamine and N-methyl-4-piperidone.

Example 220 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3-methylpiperidin-1-yl)ethanone(Compound 401)

A mixture of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid(50 mg, 0.205 mmol), 3-methyl piperidine (19 mg, 0.205 mmol), DCC (46mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough Celite and concentrated using rotary evaporator afforded 34.2 mgof2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3-methylpiperidin-1-yl)ethanoneas TFA Salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 221 Preparation of2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-8-carboxylicacid (Compound 402)

To a solution of2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-8-carboxylicacid (1.0 g, 4.09 mmol) in NMP (7.8 ml), powdered KOH (2.3 g, 40.9 mmol)was added and stirred for 10 min at 25 deg C. After which2-(trifluoromethyl)-5-vinylpyridine (1.4 g, 8.1 mmol) was added slowlyto the above solution and stirred for 14 h at 45 deg C. After completionof the react ion (monitored by LCMS), DM water was added to the crudeand extracted with the ethyl acetate. The organic layer was separated,dried and concentrated. The resulting crude was purified byreverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05%TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in30 min, injection vol. 5 mL) to obtain 15 mg of2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-8-carboxylicacid as a TFA salt.

Example 222 Preparation of8-Chloro-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2-(3-trifluoromethyl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 403)

To a stirred solution ofN-(4-Chloro-phenyl)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-hydrazinehydrochloride (0.13 g, 0.5 mmol) in absolute ethanol (5 mL) was added1-(3-Trifluoromethyl-phenyl)-piperidin-4-one (0.122 g, 0.5 mmol) at RTand then refluxed for 1 h. After completion (TLC), ethanol wasevaporated. The crude was purified by preparative HPLC to providedesired compound as brown colored solid (0.02 g, 10% yield)8-Chloro-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2-(3-trifluoromethyl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.020 g, 0.0425 mmol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.0053 g, 0.0425 mmol) in 1.5 mL THF was addedand stirred for 30 min at RT. Precipitate was filtered and dried to giveoxalate salt as brown solid (0.01 g, 43% yield).

Example 223 Preparation of8-Chloro-7-fluoro-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 404)

To a solution of8-Chloro-7-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.3 g, 1.25 mmol) in N-methyl 2-pyrolidone (1.5 mL) was added powderedpotassium hydroxide (0.7 g, 12.5 mmol) and allowed to stir for 10 min atRT. 2-trifluoromethyl-5-vinyl pyridine (0.44 g, 3.7 mmol) was added andstirred at 120 deg C. for further 24 h. After completion (TLC), reactionmixture was diluted with water (15 mL) and extracted with ethyl acetate(3×150 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure. The crude was purified throughcolumn chromatography (6% Methanol:DCM in silica 100-200 mesh, Diameterof column—2.5 cm, Height of silica—approx. 5 inch) then further purifiedthrough preparative HPLC to give the desired compound 10 as light yellowsolid (0.080 g, 21% yield).8-Chloro-7-fluoro-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.08 g, 0.22 mmol) was dissolved in THF (2.0 mL). A solution of oxalicacid dihydrate (0.028 g, 0.22 mmol) in THF (1.0 mL) was added andstirred for 30 min at RT, Precipitate obtained was filtered and dried togive oxalate salt as white solid (0.070 g, 70% yield).

Example 224 Preparation of5-(2-(6-cyclopropylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 405)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-cyclopropyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 225 Preparation of8-chloro-5-(2-(6-cyclopropylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 406)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-cyclopropyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 226 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol(Compound 407)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(4-fluorophenyl)-2-methyloxirane (400 mg, 2.1 mmol, 1.6 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 227 Preparation of5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)pyridin-2(1H)-one(Compound 408)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 228 Preparation of5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)pyridin-2(1H)-one(Compound 409)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 229 Preparation of5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-1-methylpyridin-2(1H)-one(Compound 410)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,1-methyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 230 Preparation of1-cyclopropyl-5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)pyridin-2(1H)-one(Compound 411)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,1-cyclopropyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 231 Preparation of5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)-1-methylpyridin-2(1H)-one(Compound 412)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,1-methyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 232 Preparation of5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)-1-cyclopropylpyridin-2(1H)-one(Compound 413)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,1-cyclopropyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 233 Preparation of1-(trifluoromethyl)-5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)pyridin-2(1H)-one(Compound 414)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,1-(trifluoromethyl)-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 234 Preparation of5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)-1-(trifluoromethyl)pyridin-2(1H)-one(Compound 415)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,1-(trifluoromethyl)-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMPat a temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 235 Preparation of8-chloro-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 416)

The title compound is prepared from a mixture of8-chloro-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 236 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 417)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-4-methylpiperazine, 4-chlorophenylhydrazinehydrochloride, triethylamine and N-methyl-4-piperidone

Example 237 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 418)

LAH (0.022 g, 0.58 mmol) was charged in dry THF (3 mL) and cooled to 0deg C.,2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-methylpiperazin-1-yl)ethanone(0.05 g, 0.147 mmol) was added to it portion wise. The reaction mixturewas refluxed for 4 h. The reaction mixture was cooled to 0 deg C. andquenched with sat. Na2SO4. The solid formed was filtered through celite,washed with THF, dried over Na2SO4 and concentrated under reducedpressure to obtain 11 mg of2,8-dimethyl-5-(2-(4-methylpiperazin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoleas TFA salt after purification by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 238 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(1-methylisoquinolin-4-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 420)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,1-methyl-4-vinylisoquinoline and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 239 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(1-methylisoquinolin-4-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 421)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,1-methyl-4-vinylisoquinoline and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 240 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(quinolin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 422)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,3-vinylquinoline and KOH (5-7 equiv) in NMP at a temperature rangingbetween 25 deg C. to 100 deg C. The product obtained is isolated bypreparative HPLC.

Example 241 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(quinolin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 423)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 3-vinylquinolineand KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to100 deg C. The product obtained is isolated by preparative HPLC.

Example 242 Preparation of8-Chloro-2-methyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 424)

To a solution of8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g,0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.19 g, 3.4 mmol) and allowed to stir for 10 min atRT. 5-vinyl pyrimidine (0.177 g, 1.7 mmol) was added and stirred forfurther 5 h at 60 deg C. After completion (TLC), reaction mixture wasdiluted with water (15 mL) and extracted with ethyl acetate (3×100 mL).The organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude was purified throughcolumn chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch), Then further purifiedby preparative TLC, to give the desired compound as yellow oil (0.030 g,14% yield).8-Chloro-2-methyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.025 g, 0.076 mmol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.0096 g, 0.076 mol) in THF (1.0 mL) was addedand stirred for 30 min at RT, precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.025 g, 78% yield).

Example 243 Preparation of5-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 425)

2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.75mmole), 3-(trifluoromethyl)-5-vinylpyridine (0.13 g, 0.75 mmole) and,tetra butyl ammonium chloride (2 mg, 0.0375 mmole) were charged in 5 ml,50% aqueous NaOH. The reaction mixture at 100° C. for 8 hrs. Thereaction mass was cool at RT, added 5 ml water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate,concentrated and purified by Prep HPLC to get2,8-dimethyl-5-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg).

Example 244 Preparation of8-chloro-5-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 426)

8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.165 g,0.75 mmol), 3-(trifluoromethyl)-5-vinylpyridine (0.13 g, 0.75 mmol) andtetra butyl ammonium chloride (2 mg, 0.0375 mmol) in 5 ml, 50% aqueousNaOH was heated at 100° C. for 8 hrs. The reaction mixture was cooled atRT, added 5 ml water and extracted with ethyl acetate. Dried onanhydrous sodium sulphate and concentrated and submitted for Prep HPLCto get8-chloro-2-methyl-5-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

Example 245 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 427)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,1-methyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine and KOH (5-7 equiv) in NMP ata temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 246 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 428)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,1-methyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine and KOH (5-7 equiv) in NMP ata temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 247 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(5-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 429)

Tetra butyl ammonium chloride (0.013 g, 0.0469 mmol) was taken in 2 mlof 50% aq. NaOH solution, stirred for 15 min at RT. Then added2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 2.49mmol) in it, stirred for 10 min at RT, then added3-methyl-5-vinylpyridine (0.13 g, 1.1 mmol). Reaction mixture wasstirred at 120° C. for overnight. Reaction mixture cooled to RT,quenched with water and extracted with ethyl acetate. Organic layer wasdried over anhydrous sodium sulfate, concentrated and purified byreverse phase chromatography to afford 5 mg of,(2,8-dimethyl-5-(2-(5-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole)as TFA salt.

Example 248 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(5-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 430)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,3-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 249 Preparation of2,3,4,5-tetrahydro-5-(2-(6-methoxypyridin-3-yl)ethyl)-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 431)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 250 Preparation of8-chloro-2,3,4,5-tetrahydro-5-(2-(6-methoxypyridin-3-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indole(Compound 432)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 251 Preparation of5-(2-(6-ethoxypyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 433)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 252 Preparation of8-chloro-5-(2-(6-ethoxypyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 434)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 253 Preparation of5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-N,N-dimethylpyridin-2-amine(Compound 435)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,N,N-dimethyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 254 Preparation of5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)-N,N-dimethylpyridin-2-amine(Compound 436)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,N,N-dimethyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 255 Preparation ofN-(5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-3-methylpyridin-2-yl)acetamide(Compound 437)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,N-(3-methyl-5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP ata temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 256 Preparation ofN-(5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)-3-methylpyridin-2-yl)acetamide(Compound 438)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,N-(3-methyl-5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP ata temperature ranging between 25 deg C. to 100 deg C. The productobtained is isolated by preparative HPLC.

Example 257 Preparation of5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-N-isopropylpyridin-2-amine(Compound 439)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,N-isopropyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 258 Preparation of5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)-N-isopropylpyridin-2-amine(Compound 440)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,N-isopropyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 259 Preparation of5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-N-methylpyridin-2-amine(Compound 441)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,N-methyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 260 Preparation of5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)-N-methylpyridin-2-amine(Compound 442)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,N-methyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 261 Preparation of5-(2-(5-chloropyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 443)

Tetra butyl ammonium chloride (0.034 g, 0.124 m mole) was taken in 15ml, 50% aq. NaOH solution. Stir for 15 min. at RT, Then added2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.500 gm, 2.49mmole) in it. Stir for 10 min. at RT. 3-chloro-5-vinylpyridine (0.381gm, 2.74 mmole) was added heated the reaction mixture at 100 deg C. for12-15 hrs. The reaction mixture allowed to cool at RT, extracted withethyl acetate, dried on anhydrous sodium sulphate, concentrated andpurified by Reverse Phase to get pure compound TFA Salt (510 mg). ThisTFA Salt Convert into Oxalate Salt (345 mg).

Example 262 Preparation of8-chloro-5-(2-(5-chloropyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 444)

Tetra butyl ammonium chloride (0.044 g, 0.159 mmol) was taken in 10 ml,50% aq. NaOH solution and stirred for 15 minutes at RT.8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.700 gm,3.18 mmole) was added and further stirred for 10 minutes at RT.3-chloro-5-vinylpyridine (0.486 gm, 3.49 mmole) was added and reactionmixture was heated at 100° C. for 12-15 hrs. The reaction mixture wascooled at RT, extracted with ethyl acetate dried over anhydrous sodiumsulphate, concentrated and purified by Reverse Phase to get TFA Salt(750 mg). TFA Salt was converted into Oxalate Salt (485 mg).

Example 263 Preparation of5-(2-(5-fluoropyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 445)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,3-fluoro-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 264 Preparation of8-chloro-5-(2-(5-fluoropyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 446)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,3-fluoro-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 265 Preparation ofN-(5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)pyridin-2-yl)acetamide(Compound 447)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,N-(5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 266 Preparation ofN-(5-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)ethyl)pyridin-2-yl)acetamide(Compound 448)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,N-(5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 267 Preparation of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol(Compound 449)

A mixture of compound2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.5 g, 7.5 mmol,1 equiv.) and NaH (252 mg, 10.5 mmol, 1.4 equiv) in 30 ml of DMF wereheated to 12° C., 1 h. It was cooled to RT and compound2-methyl-5-(2-methyloxiran-2-yl)pyridine (2.46 g, 16.5 mmol, 2.2 equiv)in 17 ml DMF was added dropwise over 12 min. The temperature was againraised to 120 deg C. and stirred for 3 h. The reaction mixture wascooled to RT and 5 ml of water was added to it, diluted with 700 ml ofethyl acetate and the organic part was washed with water (100 ml×3) andthen with brine. It was dried over sodium sulphate and concentratedunder vacuum. Column purified over 230-400 silica gel using a gradientof 10-20% methanol in ethyl acetate. Yield: 2.3 g (87%)

Example 268 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)propyl)-1H-pyrido[4,3-b]indole(Compound 450)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,2-methyl-5-(prop-1-en-2-yl)pyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 269 Preparation of2,3,4,5-tetrahydro-2,8-dimethyl-5-((1-(6-methylpyridin-3-yl)cyclopropyl)methyl)-1H-pyrido[4,3-b]indole(Compound 451)

The title compound is prepared by following Method 8 by using5-(1-(bromomethyl)cyclopropyl)-2-methylpyridine,(4-methylphenylhydrazinehydrochloride), triethylamine and N-methyl-4-piperidone.

Example 270 Preparation of2,8-Dimethyl-5-[2-(6-propyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 452)

To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min atRT. 2-Propyl-5-vinyl-pyridine (0.18 g, 0.5 mol) was added and stirredfor further 15 h. at 100 deg C. After completion (TLC), reaction mixturewas diluted with water (15 mL) and extracted with ethyl acetate (3×50mL). The organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The crude was purified throughcolumn chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter ofcolumn—2.5 cm, Height of silica—approx. 5 inch), Then further purifiedby preparative TLC, to give the desired compound as yellow oil (0.015 g,9% yield).2,8-Dimethyl-5-[2-(6-propyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.015 g, 0.043 mmol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.006 g, 0.043 mmol) in THF (1.0 mL) was addedand stirred for 30 min at RT, Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.008 g, 42% yield).

Example 271 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-3-yl)ethanol(Compound 453)

Carboline (500 mg, 2.5 mmol) was dissolved in DMF (5 mL). To thissolution was added NaH (60%, 180 mg, 4.5 mmol) at RT and the reactionmixture was stirred for 10-15 min after which 3-(oxiran-2-yl)pyridine(450 mg, 3.7 mmol) was added. The reaction mixture was stirred at RT for4 h (monitored by LCMS). Work up: The reaction mixture was poured on icewater and extracted with ethyl acetate. The organic layer was dried onsodium sulfate and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC to obtain 420 mg of product as whitesolid (TFA salt). TLC (silica gel) 5:95 MeOH:DCM, Rf 0.1 was observed.

Example 272 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-3-yl)ethanol(Compound 454)

Chloro carboline (500 MG, 2.27 mmol) was taken in DMF. NaH (180 mg, 4.5mmol) was added at RT and stirred for 10-15 min. Neat epoxide (450 mg,3.7 mmol) was added to it drop wise at RT. Reaction was stirred at RTfor 4 h (monitored by LCMS). RM was poured on ice water and extractedwith ethyl acetate. dried and concentrated and residue was purified byRP-HPLC. 465 mg of product as white solid (TFA salt). TLC 5% MeOH-DCM Rf0.1 was observed.

Example 273 Preparation of5-(2-(4-fluorophenyl)propyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 456)

A mixture of compound5-((Z)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indoleand5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(of ratio 1:3, 1.8 g, 5.38 mmol, 1 equiv) were shaken in a 250 ml ParrShaker vessel with 180 mg of Pd/C in 50 ml of Methanol/acetic acid(10:1) mixture for 18 hours under 60 psi H2. It was filtered over acelite bed with methanol and evaporated under vacuum. The residue wasdiluted with ethyl acetate (500 ml) and washed with 50 ml of satd.sodium bicarbonate solution and then brine. The organic part wasconcentrated under reduced pressure and column purified over 100-200silica gel using 0 to 50% ethyl acetate in hexanes as eluant, at aninterval of 5%. Yield: 685 mg (38%).

Example 274 Preparation of2-(4-fluorophenyl)-1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-2-ol(Compound 457)

A mixture of compound2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.6 g, 13.1mmol, 1 equiv.) and NaH (55%, 750 mg, 17.2 mmol, 1.3 equiv.) in 60 ml ofTHF was heated to 120 deg C. for 1 h. It was then cooled to RT andcompound 2-(4-fluorophenyl)-2-methyloxirane (4 g, 26 mmol, 2 equiv.) in25 ml of DMF was added dropwise for 5 mins at RT followed by heating at120 deg C. for 2 h. It was cooled to RT and 10 ml of water was addedfollowed by dilution with 800 ml of ethyl acetate, which was firstwashed with water (150 ml×3) and then brine, dried over sodium sulphateand concentrated under vacuum. Column purified over 230-400 Silica gel(flash) using 15% methanol in ethyl acetate as eluent. Yield: 3 g (66%).

Example 275 Preparation of tert-butyl4-(2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetyl)piperazine-1-carboxylate(Compound 458)

2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)aceticacid (0.2 g, 0.719 mmol) in 10 mL of DCM was taken, EDCI.HCl (137 mg,0.719 mmol) was added and stirred for 10 min at RT. N-Boc piperazine(133 mg, 0.719 mmol) was added to the reaction mixture and stirred for24 h at RT. Reaction was monitored by TLC & LCMS. After completion ofthe reaction, reaction mixture was concentrated and purified by columnchromatography (neutral alumina; 2% Methanol-DCM) then purified byreverse phase chromatography to afford 90 mg of tert-butyl4-(2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetyl)piperazine-1-carboxylate.

Example 276 Preparation of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperazin-1-yl)ethanone(Compound 459)

2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid(0.57 g, 2.2 mmol) was taken in DCM, cooled to 0° C., oxalyl chloride(0.228 mL, 2.6 mmol) was added, followed by the addition of DMAP(catalytic amount) and stirred for 1 h at RT. Solvent was evaporatedunder nitrogen, N-methyl piperazine (0.269 mg, 2.4 mmol) and DMAP (80mg) in DCM was added slowly drop wise at RT (under nitrogen) and stirredat RT for 30 min. Reaction mixture was quenched with water, neutralizedwith 10% NaHCO3 solution and extracted with ethyl acetate. Organic layerwas dried over anhydrous sodium sulfate and evaporated to dryness. Crudeproduct was purified by reverse phase chromatography to afford 100 mg of2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-methylpiperazin-1-yl)ethanoneas TFA salt.

Example 277 Preparation of8-chloro-5-(2-(4-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 460)

The title compound is prepared from a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 278 Preparation of5-(2-(4-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(Compound 461)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 279 Preparation of8-ethyl-5-(2-(4-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 462)

The title compound is prepared from a mixture of8-ethyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 280 Preparation of5-(2-(4-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole(Compound 463)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole,4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 281 Preparation of8-chloro-5-(2-(2-ethyl-1H-pyrrol-1-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(Compound 464)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-2-ethyl-1H-pyrrole,(4-chlorophenylhydrazinehydrochloride), triethylamine and N-methyl-4-piperidone

Example 282 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(2,4-dimethyl-1H-pyrrol-1-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 465)

The title compound is prepared by following Method 8 by using1-(2-bromoethyl)-2,4-dimethyl-1H-pyrrole,(4-chlorophenylhydrazinehydrochloride), triethylamine and N-methyl-4-piperidone

Example 283 Preparation of5-(2-(1,2,3,4-tetrahydro-8-(hydroxymethyl)-2-methylpyrido[4,3-b]indol-5-yl)ethyl)pyridine-2-carboxylicacid (Compound 466)

The title compound is prepared from a mixture of(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)methanol,5-vinylpyridine-2-carboxylic acid and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 284 Preparation of2,3,4,5-tetrahydro-5-(2-(6-(hydroxymethyl)pyridin-3-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylicacid (Compound 467)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid,(5-vinylpyridin-2-yl)methanol and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 285 Preparation of(5-(2-(8-(hydroxymethyl)-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)pyridin-2-yl)methanol(Compound 468)

The title compound is prepared from a mixture of(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)methanol,(5-vinylpyridin-2-yl)methanol and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 286 Preparation of5-(2-(6-carboxypyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylicacid (Compound 469)

The title compound is prepared from a mixture of2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid,5-vinylpyridine-2-carboxylic acid and KOH (5-7 equiv) in NMP at atemperature ranging between 25 deg C. to 100 deg C. The product obtainedis isolated by preparative HPLC.

Example 287 Preparation of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-propylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 476)

To a solution of8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g.0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powderedpotassium hydroxide (0.20 g, 0.0036 mol) and allowed to stir for 10 minat RT. 2-propyl-5-vinyl-pyridine (0.2 g, 0.00136 mol) was added andstirred for further 24 h. at 100° C. After completion (TLC), reactionmixture was diluted with water (10 mL) and extracted with ethyl acetate(3×50 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure using rotary evaporator. Thecrude was semi-purified through column chromatography (7% MeOH:DCM insilica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx.5 inch), Then further purified by preparative TLC, to give the desiredcompound as yellow oil (0.016 g, 9.6% yield).8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.016 g, 0.0000435 mol) was dissolved in THF (1.0 mL). A solution ofoxalic acid dihydrate (0.005 g, 0.00007 mol) in THF (0.5 mL) was addedand stirred for 30 min at RT. Precipitate obtained was filtered anddried to give oxalate salt as off white solid (0.010 g, 52% yield).

Example 288 Preparation of7-aza-2-methyl-5-(2-(pyridin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 481)

To a solution of tetra n-butyl ammonium chloride (0.0075 g, 0.04 mmole)in 50% aq NaOH (3 mL) was added7-aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.075 g, 0.4mmole) and 2-vinyl pyridine (0.047 g, 0.44 mmole). Then heated at 90 degC. for 7 h. Reaction was monitored by LCMS, TLC. After completereaction, mixture was quenched with water and extracted with Ethylacetate. Combined organic layers dried over sodium sulphate andconcentrated under reduced pressure afforded 4 mg of the product as aTFA salt after purification by reverse-phase chromatography (C-18, 500mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 289 Preparation of9-aza-2-methyl-5-(2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 482)

To a solution of tetra n-butyl ammonium chloride (0.017 g, 0.09 mmole)in 50% aq NaOH (5 mL) was added9-aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.17 g, 0.9mmole) and 4-vinyl pyridine (0.107 g, 1 mmole). Then heated at 90 deg C.for 7 h. Reaction was monitored by LCMS, TLC. After complete reaction,mixture was quenched with water and extracted with Ethyl acetate.Combined organic layers dried over sodium sulphate and concentratedunder reduced pressure afforded 3 mg of the product as a TFA salt afterpurification by reverse-phase chromatography (C-18, 500 mm×50 mm, MobilePhase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% Bto 80% B in 30 min, injection vol. 5 mL).

Example 290 Preparation of7-aza-2-methyl-5-(2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 483)

To a solution of tetra n-butyl ammonium chloride (0.017 g, 0.09 mmole)in 50% aq NaOH (5 mL),7-aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.17 g, 0.9mmole) and 4-vinyl pyridine (0.107 g, 1 mmole) was added then heated at90 deg C. for 7 h. Reaction was monitored by LCMS, TLC. After completereaction, mixture was quenched with water and extracted with Ethylacetate. Combined organic layers dried over sodium sulphate andconcentrated under reduced pressure afforded 5 mg of product as a TFAsalt after purification by reverse-phase chromatography (C-18, 500 mm×50mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 291 Preparation of9-aza-2-methyl-5-(2-(pyridin-2-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 484)

To a solution of tetra n-butyl ammonium chloride (0.0075 g, 0.04 mmole)in 50% aq NaOH (3 mL)9-aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.075 g, 0.4mmole) and 2-vinyl pyridine (0.047 g, 0.44 mmole) was added then heatedat 90 deg C. for 7 h. Reaction was monitored by LCMS, TLC. Aftercomplete reaction, mixture was quenched with water and extracted withEthyl acetate. Combined organic layers dried over sodium sulphate andconcentrated under reduced pressure afforded 2 mg of product as a TFAsalt after purification by reverse-phase chromatography (C-18, 500 mm×50mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile,Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

Example 292 Preparation of2,3,4,5-tetrahydro-8-iodo-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole(Compound 485)

To a solution of8-Iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g. 0.0016mol) in N-methyl 2-pyrolidone (5 mL) was added powdered potassiumhydroxide (0.9 g, 0.016 mol) and allowed to stir for 10 min at RT.2-Methyl-5-vinyl-pyridine (0.969 g, 0.0048 mol) was added and stirredfor further 24 hours at 100° C., after completion (TLC), reactionmixture was diluted with water (50 mL) and extracted with ethyl acetate(3×150 mL). The organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure using rotary evaporator. Thecrude was semi-purified through column chromatography (6% Methanol:DCMin silica 100-200 mesh, Diameter of column—2.5 cm, Height ofsilica—approx. 5 inch), then further purified by preparative HPLC to getthe desired compound as brown solid (0.105 g, 15.2% yield).8-Iodo-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.095 g, 0.00022 mol) was dissolved in THF (2.0 mL). A solution ofoxalic acid dihydrate (0.0277 g, 0.00022 mol) in THF (2.0 mL) was addedand stirred for 30 min at RT. The precipitate was filtered and dried togive oxalate salt as off white solid (0.09 g, 79% yield).

Example 292 Preparation of2-(1,2,3,4-tetrahydro-8-iodo-2-methylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)ethanone(Compound 486)

Sodium hydride was washed with hexane for removal of oil and dried undervacuum. Then sodium hydride was taken in THF. To this solution8-iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.32mmol) in THF was added drop wise at 0° C. Then reaction mixture stirredfor 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone in THFwas added drop wise in reaction mixture. Then reaction mixture stirredat rt for 2 h. Reaction monitored by TLC, after completion of reaction,reaction mixture quench with ice-water. THF was evaporated and aqueouslayer was extracted with ethyl acetate. Organic layer was dried overanhydrous sodium sulphate. The crude compound was purified by columnchromatography to gives 25 mg of desired compound. Out of that 5 mg wasstirred with ethanolic HCl to give HCl salt of2-(8-iodo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.

Example 294 Preparation of8-bromo-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 487)

Tetra butyl ammonium chloride (0.026 g, 0.094 mmol) was taken in 15 ml,50% aq. NaOH solution (7 ml) and stirred for 15 minutes at RT.8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.500 gm,1.89 mmole) was added and further stirred for 10 min. at RT.2-methyl-5-vinylpyridine (0.247 gm, 2.08 mmole) was added and reactionmixture was heated at 100° C. for 12-15 hrs. The reaction mixture wascooled at RT, extracted with ethyl acetate, dried over anhydrous sodiumsulphate, concentrated and purified by Reverse Phase HPLC to get 63 mg8-bromo-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoleas TFA Salt.

Example 295 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol(Compound 488)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(4-methoxyphenyl)-2-methyloxirane (400 mg, 2.43 mmol, 1.85 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dihydrate

Example 296 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ol(Compound 489)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(trifluoromethyl)-5-(2-methyloxiran-2-yl)pyridine (400 mg, 1.97 mmol,1.5 equiv) was added drop wise over 5 minutes. The temperature wasraised to 120 deg C. and stirred for 2 hours. The reaction mixture wascooled to RT and partitioned between ethyl acetate (60 ml) and water (15ml). The organic layer was separated and the aqueous layer was extractedwith ethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 297 Preparation of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol(Compound 490)

Sodium hydride (38 mg, 1.6 mmol, 1.14 equiv.) was added to a solution of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (290 mg, 1.4mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120° C. for 1 hour withstirring. The reaction mixture was cooled to 0° C. and3-(2-methyloxiran-2-yl)pyridine (400 mg, 2.96 mmol, 2.1 equiv) was addeddrop wise over 5 minutes. The temperature was raised to 120° C. andstirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 298 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol(Compound 491)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg, 1.3mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1 hourwith stirring. The reaction mixture was cooled to 0 deg C. and3-(2-methyloxiran-2-yl)pyridine (400 mg, 2.96 mmol, 2.3 equiv) was addeddrop wise over 5 minutes. The temperature was raised to 120 deg C. andstirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 299 Preparation of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol(Compound 492)

Sodium hydride (38 mg, 1.6 mmol, 1.14 equiv.) was added to a solution of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (290 mg, 1.4mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1 hourwith stiffing. The reaction mixture was cooled to 0 deg C. and4-(2-methyloxiran-2-yl)pyridine (400 mg, 2.96 mmol, 2.1 equiv) was addeddrop wise over 5 minutes. The temperature was raised to 120 deg C. andstirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 300 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol(Compound 493)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg, 1.3mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120° C. for 1 hour withstiffing. The reaction mixture was cooled to 0° C. and4-(2-methyloxiran-2-yl)pyridine (400 mg, 2.96 mmol, 2.3 equiv) was addeddrop wise over 5 minutes. The temperature was raised to 120° C. andstirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 301 Preparation of1-(5-(trifluoromethyl)pyridin-3-yl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanol(Compound 494)

Sodium hydride (38 mg, 1.6 mmol, 1.1 equiv.) was added to a solution of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (290 mg, 1.44mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1 hourwith stirring. The reaction mixture was cooled to 0 deg C. and3-(trifluoromethyl)-5-(oxiran-2-yl)pyridine (400 mg, 2.11 mmol, 1.5equiv) was added drop wise over 5 minutes. The temperature was raised to120 deg C. and stirred for 2 hours. The reaction mixture was cooled toRT and partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 302 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)ethanol(Compound 495)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120° C. for 1 hourwith stiffing. The reaction mixture was cooled to 0° C. and3-(trifluoromethyl)-5-(oxiran-2-yl)pyridine (400 mg, 2.1 mmol, 1.6equiv) was added drop wise over 5 minutes. The temperature was raised to120° C. and stirred for 2 hours. The reaction mixture was cooled to RTand partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 303 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol(Compound 496)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(3-fluoro-4-methoxyphenyl)oxirane (400 mg, 2.37 mmol, 1.8 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 304 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-propylpyridin-3-yl)propan-2-ol(Compound 497)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120° C. for 1 hourwith stiffing. The reaction mixture was cooled to 0° C. and5-(2-methyloxiran-2-yl)-2-propylpyridine (400 mg, 2.26 mmol, 1.72 equiv)was added drop wise over 5 minutes. The temperature was raised to 120°C. and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 305 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3,4-difluorophenyl)propan-2-ol(Compound 498)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stiffing. The reaction mixture was cooled to 0 deg C. and2-(3,4-difluorophenyl)-2-methyloxirane (400 mg, 2.4 mmol, 1.8 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dihydrate.

Example 306 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chlorophenyl)propan-2-ol(Compound 499)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120° C. for 1 hourwith stiffing. The reaction mixture was cooled to 0° C. and2-(4-chlorophenyl)-2-methyloxirane (400 mg, 2.4 mmol, 1.8 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120° C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 307 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chloro-3-fluorophenyl)propan-2-ol(Compound 500)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(4-chloro-3-fluorophenyl)-2-methyloxirane (400 mg, 2.15 mmol, 1.6equiv) was added drop wise over 5 minutes. The temperature was raised to120 deg C. and stirred for 2 hours. The reaction mixture was cooled toRT and partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 308 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3,4-dichlorophenyl)propan-2-ol(Compound 501)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(3,4-dichlorophenyl)-2-methyloxirane (400 mg, 1.97 mmol, 1.5 equiv)was added drop wise over 5 minutes. The temperature was raised to 120deg C. and stirred for 2 hours. The reaction mixture was cooled to RTand partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 309 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-chloro-4-fluorophenyl)propan-2-ol(Compound 502)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(3-chloro-4-fluorophenyl)-2-methyloxirane (400 mg, 2.14 mmol, 1.6equiv) was added drop wise over 5 minutes. The temperature was raised to120 deg C. and stirred for 2 hours. The reaction mixture was cooled toRT and partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 310 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4-difluorophenyl)propan-2-ol(Compound 503)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(2,4-difluorophenyl)-2-methyloxirane (400 mg, 2.4 mmol, 1.8 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 311 Preparation of1-(8-fluoro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol(Compound 504)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stiffing. The reaction mixture was cooled to 0 deg C. and2-(4-fluorophenyl)-2-methyloxirane (400 mg, 2.63 mmol, 2.0 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 312 Preparation of1-(8-chloro-2-cyclopropyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol(Compound 505)

Sodium hydride (38 mg, 1.6 mmol, 1.36 equiv.) was added to a solution of8-chloro-2-cyclopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (290mg, 1.18 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120° C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(4-fluorophenyl)-2-methyloxirane (400 mg, 2.63 mmol, 2.2 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dihydrate

Example 313 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-phenylpropan-2-ol(Compound 506)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-methyl-2-phenyloxirane (400 mg, 2.98 mmol, 2.3 equiv) was added dropwise over 5 minutes. The temperature was raised to 120 deg C. andstirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dihydrate

Example 314 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4,6-trifluorophenyl)propan-2-ol(Compound 507)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0° C. and2-(2,4,6-trifluorophenyl)-2-methyloxirane (400 mg, 2.1 mmol, 1.6 equiv)was added drop wise over 5 minutes. The temperature was raised to 120deg C. and stirred for 2 hours. The reaction mixture was cooled to RTand partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 315 Preparation of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)butan-2-ol(Compound 508)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(4-fluorophenyl)-2,3-dimethyloxirane (400 mg, 2.4 mmol, 1.8 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120 deg C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 316 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4-dichlorophenyl)propan-2-ol(Compound 509)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(2,4-dichlorophenyl)-2-methyloxirane (400 mg, 1.96 mmol, 1.5 equiv)was added drop wise over 5 minutes. The temperature was raised to 120deg C. and stirred for 2 hours. The reaction mixture was cooled to RTand partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 317 Preparation of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)butan-2-ol(Compound 510)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120° C. for 1 hourwith stiffing. The reaction mixture was cooled to 0° C. and2-ethyl-2-(4-fluorophenyl)oxirane (400 mg, 2.4 mmol, 1.8 equiv) wasadded drop wise over 5 minutes. The temperature was raised to 120° C.and stirred for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate (60 ml) and water (15 ml). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (1×20 ml). The combined organic layer was washed with water andfollowed by brine, dried over sodium sulphate and concentrated undervacuum to provide the crude product. The product was purified by flashcolumn chromatography over silica gel (230-400 mesh, deactivated with 1%triethylamine/hexane) using a gradient of 5 to 15% methanol/ethylacetate to yield the free base. Pure compound was converted to itsoxalate salt. The analytical sample was prepared by dissolving free basein 10 mL THF and treatment with 1 equiv. of oxalic acid dehydrate.

Example 318 Preparation of3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-ol(Compound 511)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-(trifluoromethyl)-2-(4-fluorophenyl)oxirane (400 mg, 1.94 mmol, 1.48equiv) was added drop wise over 5 minutes. The temperature was raised to120 deg C. and stirred for 2 hours. The reaction mixture was cooled toRT and partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 319 Preparation of2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-cyclopropyl-1-(4-fluorophenyl)ethanol(Compound 512)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol, 1.0 equiv.) in DMF (6 ml), and heated to 120 deg C. for 1hour with stirring. The reaction mixture was cooled to 0 deg C. and2-cyclopropyl-2-(4-fluorophenyl)oxirane (400 mg, 2.2 mmol, 1.71 equiv)was added drop wise over 5 minutes. The temperature was raised to 120deg C. and stirred for 2 hours. The reaction mixture was cooled to RTand partitioned between ethyl acetate (60 ml) and water (15 ml). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (1×20 ml). The combined organic layer was washed withwater and followed by brine, dried over sodium sulphate and concentratedunder vacuum to provide the crude product. The product was purified byflash column chromatography over silica gel (230-400 mesh, deactivatedwith 1% triethylamine/hexane) using a gradient of 5 to 15%methanol/ethyl acetate to yield the free base. Pure compound wasconverted to its oxalate salt. The analytical sample was prepared bydissolving free base in 10 mL THF and treatment with 1 equiv. of oxalicacid dehydrate.

Example 320 Preparation of2-(8-bromo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone(Compound 516)

Sodium hydride (0.6 g, 15 mmol) washed with hexane for removal of oiland dried under vacuum. Then sodium hydride was taken in THF. To thissolution 8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2g, 7.5 mmol) in THF was added drop wise at 0° C. Then reaction mixturestirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone(1.8 g, 11.3 mmol) in THF was added drop wise in reaction mixture. Thenreaction mixture stirred at rt for 2 h. Reaction was monitored by TLC.After completion of the reaction, reaction mixture quench withice-water. THF was evaporated and aqueous layer was extracted with ethylacetate. Organic layer was dried over anhydrous sodium sulphate. Thecrude compound was washed with hexane and diethyl ether for removal ofcolor impurities then recrystallized by using methanol to gives 1.5 g ofdesired compound then out of that 0.8 g compound was stirred inethanolic HCl to give HCl salt of2-(8-bromo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.

Example 321 Preparation of8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carbaldehyde(Compound 517)

The title compound is prepared from a mixture of3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indole-2(5H)-carbaldehyde,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 322 Preparation of2-butyl-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound 518)

The title compound is prepared from a mixture of2-butyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 323 Preparation of3,4-dihydro-3-hydroxy-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2H-pyrido[4,3-b]indol-1(5H)-one(Compound 316)

The title compound is prepared from a mixture of3,4-dihydro-3-hydroxy-2,8-dimethyl-2H-pyrido[4,3-b]indol-1(5H)-one,2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperatureranging between 25 deg C. to 100 deg C. The product obtained is isolatedby preparative HPLC.

Example 324 Preparation of 1,2,4-oxadiazoles G6-a-f

1,2,4-Oxadiazoles (G6) were prepared using synthetic route shown inScheme I. Pyrido[4,3-b]indoles (3), prepared by Fischer reaction, werealkylated to afford (4) by standard methods. Nitriles (4) were convertedto their corresponding hydroxyamidines (5). Cyclization of 5 with ethylcarboxylate in the presence of NaOEt gave G6.

Preparation of Hydroxyamidines (G5) from the Corresponding Nitriles (G4)

Sodium hydroxide (1 equiv.) dissolved in water was added to a solutionof hydroxylamine hydrochloride (1 equiv.) dissolved in 95% ethanol. Theappropriate nitrile (0.5 equiv.) in 95% ethanol was added to the abovesolution. The mixture was heated under reflux for 6-7 h, cooled anddiluted with water. The solid was isolated by filtration, washed withwater, ethanol and ether and recrystallized from MeOH.

Preparation of 1,2,4-oxadiazoles (G6) from the CorrespondingHydroxyamidines (G5)

A solution of appropriate hydroxyamidine (0.6-1 equiv), of ethylbenzoate (1 equiv.) and of sodium ethoxide (1 equiv.) was heated underreflux for 7-15 h in anhydrous ethanol. The solvent was removed underreduced pressure and the residue was partitioned between CHCl₃ andwater. The organic layer was washed with water, dried (Na₂SO₄) andevaporated. The residue was purified by chromatography on neutralaluminum oxide (EtOAc/Et₃N, 8:1).

3-(2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionitrile(G4-a)

To a solution of Pyrido[4,3-b]indole G3-a (R¹⁹═H) (2.108 g, 11.3 mmol)in mixture benzene (30 mL) and acrylonitrile (10 mL) was addedbenzyltrimethylammonium hydroxide solution (40% wt. % in methanol, 0.7mL). The mixture was heated under reflux for 1 h, cooled, washed withwater, dried over Na₂SO₄ and concentrated. Purification by columnchromatography on silica gel (benzene/Et₃N, 9:1) gave 2.174 g (80%) ofthe title compound, mp 108-110° C. (acetone, −12° C.). ¹H NMR(Acetone-d₆): 2.46 (3H, s), 2.73-3.01 (6H, m), 3.56 (2H, s), 4.48 (2H,t), 6.97-7.16 (2H, m), 7.38 (1H, d), 7.45 (1H, d).

3-(8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionitrile(G4-b) was prepared from Pyrido[4,3-b]indole G3-b (R¹⁹=Cl) in 76% yield,mp 127-129° C. (acetone, −12° C.). ¹H NMR (Acetone-d₆): 2.50 (3H, s),2.75-3.06 (6H, m), 3.58 (2H, s), 4.54 (2H, t), 7.12 (1H, dd), 7.43 (1H,d), 7.53 (1H, d).

N-Hydroxy-3-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionamidine (G5-a) was prepared in 72% yield, mp 218-219.5° C. (dec).¹H NMR (DMSO-d₆/CDCl₃, 2:1): 2.34 (2H, t), 2.48 (3H, s), 2.70-2.92 (4H,m), 3.52 (2H, s), 4.22 (2H, t), 5.48 (2H, s), 6.90-7.10 (2H, m), 7.28(1H, d), 7.40 (1H, d), 8.90 (1H, s).

N-Hydroxy-3-(8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionamidine (G5-b) was resulted in 65% yield, mp 211-213° C. (dec).¹H NMR (DMSO-d₆/CDCl₃, 2:1): 2.36 (2H, t), 2.48 (3H, s), 2.68-2.84 (4H,m), 3.52 (2H, s), 3.79 (3H, s), 4.21 (2H, t), 5.39 (2H, s), 6.67 (1H,dd), 6.77 (1H, d), 7.27 (1H, d), 8.90 (1H, s).

3-(2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)-N-hydroxypropionamidine(G5-c) was prepared in 75% yield, mp 218-220° C. (dec). ¹H NMR(DMSO-d₆/CDCl₃, 2:1): 2.36 (5H, m), 2.46 (3H, s), 2.68-2.88 (4H, m),3.49 (2H, s), 4.22 (2H, t), 5.48 (2H, s), 6.90 (1H, d), 7.10 (1H, s),7.30 (1H, d), 8.92 (1H, s).

3-(8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)-N-hydroxypropionamidine(G5-d) was prepared in 68% yield, mp 222-224° C. (dec). ¹H NMR(DMSO-d₆/CCl₄, 3:1): 2.32 (2H, t), 2.47 (3H, s), 2.73-2.92 (4H, m), 3.54(2H, s), 4.23 (2H, t), 5.50 (2H, s), 7.03 (1H, dd), 7.32 (1H, d), 7.46(1H, d), 8.87 (1H, s).

3-(8-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)-N-hydroxypropionamidine(G5-f) was prepared in 71% yield, mp 222-224° C. (dec). ¹H NMR(DMSO-d₆/CCl₄, 3:1): 2.35 (2H, t), 2.45 (3H, s), 2.72-2.92 (4H, m), 3.53(2H, s), 4.25 (2H, t), 5.55 (2H, s), 6.89 (1H, td), 7.08 (1H, dd), 7.44(1H, dd), 8.89 (1H, s).

2-Methyl-5-[2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G6-a) was prepared on a 1.0-equiv scale. Chromatographic purificationgave 60% (G6-a), mp 111-112° C. (acetone/pentane). ¹H NMR(DMSO-d₆/CDCl₃, 1:2): 2.48 (3H, s), 2.70-2.88 (4H, m), 3.15 (2H, t),3.55 (2H, s), 4.48 (2H, t), 6.90-7.08 (2H, m), 7.30 (2H, d), 7.48-7.65(3H, m), 8.80 (2H, d). Hydrochloride (G6-a), mp softening 218° C.,226-228° C. (dec) (H₂O).

8-Methoxy-2-methyl-5-[2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G6-b) was prepared on a 1.0-equiv scale. Chromatographic purificationgave 50.6% (G6-b), mp 77.5-79° C. (Et₃N, −12° C.). ¹H NMR (CDCl₃): 2.60(3H, s), 2.82-2.95 (4H, m), 3.22 (2H, t), 3.68 (2H, s), 3.88 (3H, s),4.50 (2H, t), 6.78-6.94 (2H, m), 7.28 (1H, d), 7.52-7.70 (3H, m), 8.18(2H, d). Hydrochloride (G6-b), mp 137-138° C. (H₂O).

2,8-Dimethyl-5-[2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole(G6-c) was prepared on a 1.0-equiv. scale. Chromatographic purificationgave 48% (G6-c), mp 120-120.5° C. (EtOAc/pentane). ¹H NMR(DMSO-d₆/CDCl₃, 1:2): 2.40 (3H, s), 2.48 (3H, s), 2.72-2.90 (4H, m),3.17 (2H, t), 3.57 (2H, s), 4.50 (2H, t), 6.92 (1H, d), 7.13 (1H, s),7.22 (1H, d), 7.52-7.71 (3H, m), 8.11 (2H, d). Hydrochloride (G6-c), mpsoftening 213° C., 220-223° C. (dec) (H₂O).

8-Chloro-2-methyl-5-[2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido-[4,3-b]indole(G6-d) was prepared on a 0.6-equiv. scale. Chromatographic purificationgave 64% (G6-d), mp 122-123° C. (EtOAc/pentane). ¹H NMR (CDCl₃): 2.58(3H, s), 2.83-2.98 (4H, m), 3.23 (2H, t), 3.66 (2H, s), 4.52 (2H, t),7.13 (1H, dd), 7.31 (1H, m), 7.42 (1H, d), 7.53-7.70 (3H, m), 8.17 (2H,d). Hydrochloride (G6-d), mp softening 214° C., 227-229° C. (dec) (H₂O).

2-Methyl-5-[2-(5-pyridin-4-yl-1,2,4-oxadiazol-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G6-e)

To sodium ethoxide (from 0.188 g of Na and 25 mL of anhydrous ethanol)was added ethyl isonicotinate (1.249 g, 8.3 mmol) and 5-a (1.336 g, 4.9mmol). The mixture was heated under reflux for 7 h. Solvent was removedunder reduced pressure and the residue partitioned between ethyl acetateand water. The organic layer was washed with water, dried over Na₂SO₄and evaporated. The residue was purified by chromatography on silica gel(benzene/Et₃N, 9:1) to yield 1.145 g (64.9%) of G6-e, mp 110.5-111.5° C.(i-PrOH, −12° C.). ¹H NMR (DMSO-d₆/CDCl₃, 2:1): 2.42 (3H, s), 2.64-2.90(4H, m), 3.25 (2H, t), 3.51 (2H, s), 4.53 (2H, t), 6.90-7.12 (2H, m),7.26-7.42 (2H, m), 7.98 (2H, d), 8.87 (2H, d).

8-Fluoro-2-methyl-5-[2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido-[4,3-b]indole(G6-f) was prepared on a 0.6-equiv. scale. Chromatographic purificationgave 76% (G6-f), mp 121.5-122.5° C. (EtOAc/pentane). ¹H NMR(DMSO-d₆/CDCl₃, 1:2): 2.47 (3H, s), 2.73-2.92 (4H, m), 3.20 (2H, t),3.55 (2H, s), 4.51 (2H, t), 6.82 (1H, td), 7.00 (1H, dd), 7.29 (1H, dd),7.50-7.71 (3H, m), 8.11 (2H, d). Hydrochloride (G6-f), mp 187° C.,222-224° C. (dec) (H₂O).

Example 325 Preparation of Thiazoles G8-a-f

Thiazoles (G8) were prepared using synthetic route shown in Scheme II.Nitriles (G4) were converted to their corresponding thiopropionamides(7). Cyclization of 7 with 2-bromoketone (R^(14a)—COCH₂Br) gave G8.

3-(2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)thiopropionamide(G7-a)

Solution of G4-a (3.0 g, 12.5 mmol) in pyridine (25 mL) andtriethylamine (3.5 mL) was saturated with H₂S for 15 min. The reactionmixture was concentrated in vacuo after 72 h at ambient temperature. Thesolid residue was washed with aqueous NaOH solution and with water.After drying in vacuo to yield 3.3 g (96%) of G7-a, mp 149-151° C. ¹HNMR (DMSO-d₆/CDCl₃, 1:2): 2.53 (3H, s), 2.75-3.01 (6H, m), 3.60 (2H, s),4.46 (2H, t), 6.94-7.16 (2H, m), 7.34 (1H, d), 7.43 (1H, d), 9.12 (2H,s).

Other thiopropionamides 7 were prepared by the above method for G7-a.

3-(8-Methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)thiopropionamide(G7-b) was prepared in 89% yield, mp 145-147° C. ¹H NMR (DMSO-d₆/CDCl₃,1:2): 2.51 (3H, s), 2.74-2.98 (6H, m), 3.56 (2H, s), 3.80 (3H, s), 4.41(2H, t), 6.72 (1H, d), 6.80 (1H, s), 7.31 (1H, d), 9.09 (2H, s).

3-(2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)thiopropionamide(7G-c) was prepared in 91% yield, mp 161-164° C. ¹H NMR (DMSO-d₆/CDCl₃,1:2): 2.40 (3H, s), 2.52 (3H, s), 2.75-2.99 (6H, m), 3.57 (2H, s), 4.42(2H, t), 6.92 (1H, d), 7.13 (1H, s), 7.31 (1H, d), 9.10 (2H, s).

3-(8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)thiopropionamide(G7-e) was prepared in 91% yield, mp 156-158° C. ¹H NMR (DMSO-d₆): 2.41(3H, s), 2.66-2.94 (6H, m), 3.47 (2H, s), 4.41 (2H, t), 7.06 (1H, d),7.38 (1H, s), 7.46 (1H, d), 9.30 (1H, s), 9.51 (1H, s).

3-(8-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)thiopropionamide(G7-f) was prepared in 94% yield, mp 165-167° C. ¹H NMR (DMSO-d₆/CDCl₃,1:2): 2.52 (3H, s), 2.75-3.00 (6H, m), 3.55 (2H, s), 4.44 (2H, t), 6.84(1H, td), 6.99 (1H, dd), 7.38 (1H, dd), 9.13 (2H, s).

2-Methyl-5-[2-(4-phenylthiazol-2-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G8-a)

A mixture of G7-a (1.62 g, 5.9 mmol), 2-bromoacetophenone (1.18 g, 5.9mmol) and 5% HCl in ethanol (22 mL) was heated at reflux for 20 min. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was partitioned between CH₂Cl₂ and aqueous NaOHsolution. The organic layer was washed with water, dried (Na₂SO₄) andevaporated. Purification by column chromatography on silica gel(benzene/Et₃N, 13:1) gave 1.79 g (80.9%) of the title compound, mp142-143 (i-PrOH). ¹H NMR (DMSO-d₆/CDCl₃, 1:2): 2.48 (3H, s), 2.73 (4H,s), 3.43 (2H, t), 3.58 (2H, s), 4.53 (2H, t), 6.95-7.15 (2H, m),7.27-7.53 (6H, m), 7.90 (2H, d). Hydrochloride (G8-a), mp 128-130° C.(H₂O).

Other substituted thiazoles 8 were prepared by the above method forG8-a.

8-Methoxy-2-methyl-5-[2-(4-phenylthiazol-2-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G8-b) was prepared in 62.8% yield, mp 135-136.5° C. (heptane). H NMR(Acetone-d₆): 2.43 (3H, s), 2.61-2.77 (4H, m), 3.45-3.57 (4H, m), 3.82(3H, s), 4.58 (2H, t), 6.75 (1H, dd), 6.93 (1H, d), 7.30-7.53 (4H, m),7.74 (1H, s), 8.04 (2H, d). Hydrochloride (G8-b), mp 162-163° C. (H₂O).

2,8-Dimethyl-5-[2-(4-phenylthiazol-2-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G8-c) was prepared in 72% yield, mp 148.5-149° C. (EtOAc). ¹H NMR(DMSO-d₆/CDCl₃, 1:2): 2.41 (3H, s), 2.45 (3H, s), 2.69 (4H, s), 3.39(2H, t), 3.53 (2H, s), 4.49 (2H, t), 6.87 (1H, d), 7.06-7.20 (2H, m),7.24-7.45 (4H, m), 7.88 (2H, d). Hydrochloride (G8-c), mp 127-129° C.(H₂O).

2-Methyl-5-[2-(4-pyridin-4-yl-thiazol-2-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G8-d)

A mixture of 7-a (1.0 g, 3.7 mmol), 2-bromo-1-pyridin-4-yl-ethanonehydrobromide (1.029 g, 3.7 mmol) and 5% HCl in ethanol (44 mL) washeated at reflux for 20 min. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The residue partitioned betweenCH₂Cl₂ and aqueous NaOH solution. The organic layer was washed withwater, dried over Na₂SO₄ and evaporated. The solid residue was washedwith acetone. Recrystallization from 2-propanol afforded G8-d (0.42 g,30.6%), mp 158.5-159.5° C. ¹H NMR (DMSO-d₆/CCl₄, 1:1): 2.42 (3H, s),2.67 (4H, s), 3.44 (2H, t), 3.53 (2H, s), 4.52 (2H, t), 6.90-7.09 (2H,m), 7.27-7.40 (2H, m), 7.86 (2H, d), 8.17 (1H, s), 8.58 (2H, d).

8-Chloro-2-methyl-5-[2-(4-phenylthiazol-2-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G8-e)

A mixture of 7-e (1.033 g, 3.4 mmol), 2-bromoacetophenone (0.67 g, 3.4mmol) and 5% HCl in ethanol (20 mL) was heated at reflux for 20 min. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue partitioned between CH₂Cl₂ and aqueous NaOH solution.The organic layer was washed with water, dried over Na₂SO₄ andevaporated. Purification by column chromatography on silica gel(benzene/Et₃N, 9:1) gave 1.019 g (74%) of G8-e, mp 140-142° C. (i-PrOH).¹H NMR (Acetone-d₆): 2.42 (3H, s), 2.56-2.81 (4H, m), 3.39-3.60 (4H, m),4.60 (2H, t), 7.04 (1H, d), 7.27-7.51 (5H, m), 7.71 (1H, s), 7.98 (2H,d).

8-Fluoro-2-methyl-5-[2-(4-phenylthiazol-2-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(G8-f) was prepared in 77% yield, mp 136.5-137° C. (EtOAc). ¹H NMR(DMSO-d₆/CDCl₃, 1:2): 2.49 (3H, s), 2.74 (4H, s), 3.42 (2H, t), 3.55(2H, s), 4.53 (2H, t), 6.82 (1H, td), 7.01 (1H, dd), 7.20-7.53 (5H, m),7.90 (2H, d). Hydrochloride (G8-f), mp 135-137° C. (H₂O).

Example 326 Preparation of5-Substituted-2,4-dihydro-1,2,4-triazole-3-thiones G11-a-d

5-Substituted-2,4-dihydro-1,2,4-triazole-3-thiones (G11) were preparedusing synthetic route shown in Scheme III. Pyrido[4,3-b]indole (3) werealkylated to afford the ester (G9), which was converted to itscorresponding hydrazide (G10). Reaction of carboxylic acid hydrazides(G10) and methyl isothiocyanate afforded the2,4-dihydro-1,2,4-triazole-3-thione (G11).

3-(2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionic acidethyl ester (G9-a)

The benzyltrimethylammonium hydroxide solution (40% wt. in methanol, 3.5mL) was added to a solution of G3-a (17,114 g, 92 mmol) in mixturebenzene (170 mL) and ethyl acrylate (75 mL). The mixture was heatedunder reflux for 7 h, cooled, washed with water, and extracted with 2MHCl. The acidic solution was extracted with benzene, basified with 10%NaOH, and extracted with benzene. The combined extracts were washed withwater, dried and evaporated to an oil (21.18 g, 80%). ¹H NMR(Acetone-d₆): 1.13 (3H, t), 2.49 (3H, s), 2.70-2.96 (6H, m), 3.60 (2H,s), 4.05 (2H, q), 4.37 (2H, t), 6.94-7.15 (2H, m), 7.32-7.43 (2H, m).

Other esters 9 were prepared by the above method for 9-a.

3-(8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionicacid ethyl ester (G9-b) was prepared in 88% yield, oil. ¹H NMR(Acetone-d₆): 1.13 (3H, t), 2.45 (3H, s), 2.69-2.98 (6H, m), 3.52 (2H,s), 4.03 (2H, q), 4.39 (2H, t), 7.06 (1H, dd), 7.36 (1H, d), 7.40 (1H,d).

3-(8-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionicacid ethyl ester (G9-c) was prepared in 89% yield, oil. ¹H NMR(Acetone-d₆): 1.13 (3H, t), 2.45 (3H, s), 2.68-2.94 (6H, m), 3.51 (2H,s), 4.03 (2H, q), 4.38 (2H, t), 6.86 (1H, td), 7.06 (1H, dd), 7.37 (1H,dd).

3-(8-Methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionicacid ethyl ester (G9-d) was prepared in 80% yield, oil. ¹H NMR(Acetone-d₆): 1.15 (3H, t), 2.46 (3H, s), 2.65-2.94 (6H, m), 3.51 (2H,s), 3.78 (3H, s), 4.05 (2H, q), 4.34 (2H, t), 6.73 (1H, d), 6.89 (1H,s), 7.28 (1H, d).

3-(2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionic acidhydrazide (G10-a)

To a solution of G9-a (20.356 g, 74.8 mmol) in ethanol (50 mL) was addedhydrazine monohydrate (20 mL, 0.41 mol), and the mixture was heatedunder reflux for 2 h 30 min. After 72 h storage at −12° C., theresulting crystals were collected, washed with 2-propanol, and dried togive 12.7 g (65.6%) of G10-a, mp 123-124° C. ¹H NMR (DMSO-d₆/CCl₄, 3:1):2.32-2.47 (5H, m), 2.63-2.92 (4H, m), 3.50 (2H, s), 4.11 (2H, br s),4.26 (2H, t), 6.89-7.12 (2H, m), 7.24-7.42 (2H, m), 9.03 (1H, br s).

Other acid hydrazides G10 were prepared by the above method for G10-a.

3-(8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionicacid hydrazide (G10-b) was prepared in 74% yield, mp 172-173° C. ¹H NMR(DMSO-d₆/CDCl₃, 1:1): 2.38-2.50 (5H, m), 2.68-2.94 (4H, m), 3.50 (2H,s), 4.00 (2H, br s), 4.28 (2H, t), 7.01 (1H, dd), 7.28 (1H, d), 7.32(1H, d), 9.05 (1H, br s).

3-(8-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionicacid hydrazide (G10-c) was prepared in 72% yield, mp 158-159° C. ¹H NMR(DMSO-d₆/CCl₄, 2:1): 2.30-2.45 (5H, m), 2.67-2.92 (4H, m), 3.48 (2H, s),3.91 (2H, br s), 4.25 (2H, t), 6.82 (1H, td), 7.00 (1H, dd), 7.32 (1H,dd), 9.01 (1H, br s).

3-(8-Methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)propionicacid hydrazide (G10-d)

The solution of 9-d (20.872 g, 66 mmol) in ethanol (50 mL) and hydrazinemonohydrate (20 mL, 0.41 mol) was heated under reflux for 2 h 15 min andthen evaporated in vacuo. The residue was crystallized from ethanol(−12° C.) to yield 8.9 g (44.6%) of G10-d, mp 126.5-127.5° C. ¹H NMR(DMSO-d₆/CDCl₃, 1:1): 2.36-2.49 (5H, m), 2.67-2.94 (4H, m), 3.52 (2H,s), 3.77 (3H, s), 4.00 (2H, br s), 4.26 (2H, t), 6.69 (1H, d), 6.78 (1H,s), 7.22 (1H, d), 9.04 (1H, br s).

4-Methyl-5-[2-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)ethyl]-2,4-dihydro-1,2,4-triazole-3-thione(G11-a)

A mixture of G10-a (2.187 g, 8 mmol), methyl isothiocyanate (0.587 g, 8mmol) and 55 mL of ethanol was heated under reflux for 6 h 30 min andthen allowed to stand for 48 h at ambient temperature. The resultingcrystals were collected by filtration, washed with ethanol, and dried togive 2.268 g (86%) of G11-a, mp 216-219° C. (EtOH). ¹H NMR(DMSO-d₆/CDCl₃, 1:1): 2.45 (3H, s), 2.72 (4H, s), 3.05 (2H, t), 3.16(3H, s), 3.53 (2H, s), 4.42 (2H, t), 6.88-7.13 (2H, m), 7.22-7.38 (2H,m), 13.52 (1H, br s); MS, m/z 327 (M⁺).

Other 2,4-dihydro-1,2,4-triazole-3-thiones G11 were prepared by theabove method for G11-a.

5-[2-(8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)ethyl]-4-methyl-2,4-dihydro-1,2,4-triazole-3-thione(G11-b) was prepared in 88% yield, mp 216-219° C. (EtOH). ¹H NMR(DMSO-d₆): 2.41 (3H, s), 2.70 (4H, s), 3.06 (2H, t), 3.20 (3H, s), 3.49(2H, s), 4.42 (2H, t), 7.05 (1H, d), 7.30-7.47 (2H, m), 13.55 (1H, brs); MS, m/z 361 (M⁺).

5-[2-(8-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)ethyl]-4-methyl-2,4-dihydro-1,2,4-triazole-3-thione(G11-c) was prepared in 83% yield, mp 215-218° C. (EtOH). ¹H NMR(DMSO-d₆/CDCl₃, 2:1): 2.43 (3H, s), 2.71 (4H, s), 3.04 (2H, t), 3.16(3H, s), 3.48 (2H s), 4.41 (2H, t), 6.83 (1H, td), 7.03 (1H, dd), 7.29(1H, dd), 13.52 (1H, br s); MS, m/z 345 (M⁺).

5-[2-(8-Methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl)ethyl]-4-methyl-2,4-dihydro-1,2,4-triazole-3-thione(G11-d) was prepared in 93% yield, mp 219-222° C. (EtOH). ¹H NMR(DMSO-d₆): 2.43 (3H, s), 2.69 (4H, s), 3.05 (2H, t), 3.17 (3H, s), 3.50(2H, s), 3.77 (3H, s), 4.39 (2H, t), 6.72 (1H, dd), 6.89 (1H, d), 7.27(1H, d), 13.49 (1H, br s); MS, m/z 357 (M⁺).

The compounds prepared according to the Examples are further detailed inTable 4.

TABLE 4 Synthetic Data Ex. Comp. NMR MS HPLC HPLC No. No. Salt MWSolvent NMR Data observed Method² Rt (min) 9 25 TFA Salt 432.48 CDCl₃13.3 (bs, 1H), 7.4- 319 1 6.06 7.0 (m, 5H), 6.80- 6.70 (d, 2H), 4.7-4.6(d, 1H), 4.40-4.22 (m, 1H), 4.20-4.10 (m, 1H), 4.10-4.0 (d, 1H), 3.5-3.4(t, 1H), 3.20-3.17 (t, 1H), 3.0 (t, 2H), 2.80 (s, 3H), 2.7-2.61 (m, 1H),2.40 (s, 3H), 2.23 (s, 3H), 2.2-2.1 (m, 1H) 10 18 Free Base 442.35 CDCl₃8.10-8.0 (m, 1H), 442 1 5.617 7.60-6.80 (m, 5H), 4.50 (s, 2H), 4.2-4.0(m, 4H), 3.60 (s, 2H), 2.90-2.80 (t, 2H), 2.30 (s, 3H), 2.30-2.24 (m,2H), 1.20 (t, 3H) 39 19 Free Base 440.54 CDCl₃ 7.83 (d, 1H), 7.60- 441 14.01 7.18 (m 9H), 4.60 (s, 2H), 4.20-4.10 (t, 2H), 4.10-4.0 (q, 2H),3.60-3.50 (m, 2H), 3.00-2.95 (m, 2H), 2.90-2.89 (m, 2H), 2.45 (s, 3H),1.24-1.10 (t, 3H) 11 24 Free Base 362.46 CDCl₃ 7.4-6.9 (m, 8H,), 363 26.813 4.65-4.60 (s, 2H), 4.3-4.2 (m, 4H), 3.7- 3.6 (m, 2H), 3.0-2.99 (t,2H), 2.4-2.3 (m, 1H), 2.29-2.20 (m, 1H), 2.15 (s, 3H), 0.9 (t, 3H) 40 20Oxalate Salt 394.46 CDCl₃ 13.2 (s, 1H), 7.4-7.2 305 1 5.7 (m, 6H),6.98-6.80 (t, 2H), 4.80-4.60 (m, 1H), 4.40-4.00 (m, 3H), 3.60-3.40 (m,2H), 3.20-3.00 (m, 3H), 2.80 (s, 3H), 2.6-2.4 (m, 1H) 2.50 (s, 3H) 29139 TFA salt 419.44 CDCl₃ 8.78 (s, 1H), 7.41- 306 1 3.8 7.39 (d, 2H),7.30- 7.20 (m, 1H), 7.10- 7.00 (d, 2H), 5.55- 5.20 (dd, 2H), 4.80- 4.70(d, 1H), 4.20- 4.10 (d, 1H), 3.90- 3.80 (s, 1H), 3.40- 3.30 (m, 2H),3.10 (s, 3H), 2.90 (s, 1H), 2.75 (s, 3H), 2.40 (s, 3H) 20 21 Free Base305.42 CDCl₃ 8.6 (d, 1H), 7.9 (t, 306 1 3.81 1H), 7.58-7.50 (m, 1H), 7.1(s, 1H), 7.05-6.90 (m, 3H), 4.8-4.6 (m, 2H), 4.42-4.38 (m, 1H), 4.0 (m,1H), 3.8 (m, 1H), 3.60-3.4 (m, 2H), 3.20-3.10 (m, 1H), 3.0 (s, 3H), 3.0-2.8 (m, 2H), 2.42 (s, 3H) 21 22 Free Base 305.42 CDCl₃ 8.5 (s, 2H),7.20- 306 1 1.5, 3.77 7.15 (d, 2H),7.14- 7.06 (d, 1H), 6.90- 6.85 (d,2H), 4.30- 4.22 (t, 2H), 4.20 (bs, 2H), 3.20 (bs, 2H), 3.05 (t, 2H), 2.8(s, 3H), 2.6 (bs, 2H), 2.45 (s, 3H) 22 23 TFA Salt 433.47 CDCl₃ 8.70 (s,1H), 7.85- 320 1 3.92 7.80 (t, 1H), 7.6-7.5 (t, 1H), 7.1-6.9 (m, 4H),4.7 (t, 2H), 4.50-4.40 (t, 1H), 4.0 (d, 1H), 3.8 (m, 1H), 3.60-3.2 (m,5H), 2.9 (m, 2H), 2.4 (s, 3H), 1.5 (t, 3H) 12 37 TFA Salt 432.48 CDCl₃7.5-7.1 (m, 6H), 319 1 5.78 6.93-6.90 (m, 2H), 4.8-4.4 (m, 4H), 4.0- 3.2(m, 4H), 3.2-3.0 (m, 4H), 2.5 (s, 3H), 1.4-1.3 (t, 3H) 13 26 TFA Salt446.51 CDCl₃ 7.4-7.2 (m, 1H,), 333 1 6.04 7.2-7.1 (d, 2H), 7.06-7.0 (d,2H), 6.8-6.75 (d, 2H), 4.6- 4.2 (m, 4H), 4.2-3.2 (m, 4H), 3.20-3.15 (m,2H), 3.10-3.0 (m, 2H), 2.45 (s, 3H), 2.3 (s, 3H), 1.42-1.3 (t, 3H) 23 27TFA Salt 433.47 CDCl₃ 8.5 (d, 2H), 7.25 (d, 320 1 3.84 2H), 7.1 (s, 1H),7.0 (d, 1H), 6.9 (d, 1H), 4.75-4.65 (d, 1H), 4.4-4.3 (m, 2H), 4.1- 4.0(d, 1H), 3.94- 3.82 (m, 1H), 3.4- 3.3 (m, 1H), 3.2-3.1 (m, 3H),2.72-2.60 (m, 1H), 2.58-2.42 (m, 5H), 1.58-1.50 (t, 3H) 14 1 TFA Salt418.45 CDCl₃ 7.45-7.40 (d, 2H), 305 1 5.7 7.25-7.16 (m, 2H), 7.1-6.9 (d,2H), 6.8- 6.7 (d, 2H), 4.7 (d, 1H), 4.4-4.3 (m, 1H), 4.20-4.03 (m, 2H),3.55-3.40 (m, 1H), 3.22-3.10 (m, 1H), 3.09-2.90 (m, 2H), 2.83 (s, 3H),2.65 (m, 1H), 2.35 (s, 3H), 2.2 (m, 1H). 15 2 TFA Salt 404.43 CDCl₃7.5-7.10 (m, 7H), 291 1 5.422 6.9-6.8 (m, 2H), 4.6 (d, 1H), 4.30-4.19(m, 2H), 4.05 (d, 1H), 3.62-3.40 (m, 1H), 3.20-3.0 (m, 3H), 2.9 (s, 3H),2.7-2.6 (t, 1H), 2.2- 2.1 (t, 1H) 32 137 TFA Salt 404.43 CDCl₃ 9.6 (1H),7.5-7.19 291 1 5.28 (m, 6H), 7.0-6.9 (d, 2H), 3.79 (s, 2H), 3.6 (s, 2H),3.1-3.0 (m, 2H), 2.8-2.70 (t, 2H), 2.3 (s, 3H), 2.3 (s, 3H) 30 138 FreeBase 319.44 CDCl₃ 8.40-8.38 (s, 1H), 320 1 3.89 7.4-7.0 (m, 5H), 5.2 (s,2H), 4.07-3.9 (bs, 1H), 3.1 (bs, 1H), 2.9 (bs, 2H), 2.5 (s, 3H), 2.42(s, 3H), 2.0 (b, 2H), 1.4-1.3 (t, 3H) 33 140 TFA Salt 418.45 CDCl₃ 12.0(s, 1H), 7.5-7.0 305 1 5.86 (m, 8H), 4.10 (s, 2H), 3.61-3.5 (m, 2H),3.0-2.8 (t, 4H), 2.45 (s, 3H), 2.4-1.7 (m, 2H), 1.5 (t, 3H) 16 4 TFASalt 418.45 CDCl₃ 7.40-7.38 (m, 3H), 305 1 5.52 7.25-7.18 (m, 4H),6.9-6.8 (m, 2H), 4.70-4.60 (d, 1H), 4.40-4.36 (m, 1H), 4.23-4.10 (m,2H), 3.56-3.42 (m, 1H), 3.21-3.19 (m, 1H), 3.10-3.0 (m, 4H), 2.67-2.58(m, 1H), 2.1-2.0 (m, 1H), 1.4-1.3 (t, 3H) 17 3 TFA Salt 432.48 CDCl₃7.41-7.15 (m, 4H), 319 1 5.78 7.1-7.0 (m, 2H), 6.8- 6.7 (m, 2H), 4.70-4.60 (d, 1H), 4.40- 4.30 (m, 1H), 4.20- 4.10 (q, 2H), 3.60- 3.50 (m,1H), 3.30- 3.20 (m, 1H), 3.15- 3.0 (m, 4H), 2.6 (m, 1H), 2.30 (s, 3H),2.1 (m, 1H), 1.38 (t, 3H) 24 5 TFA Salt 419.44 CDCl₃ 8.60-8.50 (d, 2H),306 1 3.63 7.4-7.0 (m, 6H), 4.80 (d, 1H), 4.40 (t, 2H), 4.10 (d, 1H),3.9 (m, 1H), 3.60- 3.40 (m, 2H), 3.30- 3.17 (m, 4H), 2.80- 2.70 (d, 1H),1.60- 1.50 (t, 3H) 25 6 TFA Salt 419.44 CDCl₃ 8.7 (d, 1H), 7.90- 306 13.64 7.80 (t, 1H), 7.60- 7.50 (m, 1H), 7.40- 7.0 (m, 5H), 4.80- 4.70 (d,1H), 4.60- 4.50 (m, 1H), 4.1-4.0 (d, 1H), 3.90-3.80 (m, 1H), 3.60-2.8(m, 8H), 1.5 (t, 3H) 35 28 HCl salt 370.92 DMSO 10.30 (s, 1H), 7.42- 3351 5.35 7.0 (m, 7H), 5.6 (m, 1H), 4.90-4.80 (m, 1H), 4.60-4.55 (d, 1H),4.30-4.00 (m, 3H), 3.70 (s, 1H), 3.4 (m, 1H), 3.22- 3.10 (d, 1H), 3.00-2.90 (m, 3H), 2.80- 2.60 (d, 1H), 2.40 (s, 3H), 2.30 (s, 3H) 36 29 TFAsalt 462.5 CDCl₃ 13.20 (bs, 1H), 7.4- 349 1 5.48 7.0 (m, 7H), 5.05- 4.97(m, 1H), 4.70 (t, 1H), 4.25-4.10 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.10(m, 5H), , 2.5 (s, 3H), 2.38 (S, 3H), 1.41 (t, 3H) 34 16 TFA salt 404.43CDCl₃ 10.7 (s, 1H), 7.6-7.0 291 1 5.14 (m, 9H) 4.60-4.2 (m, 4H),3.55-3.40 (m, 2H), 3.30-3.20 (dd, 2H), 3.0 (bs, 2H), 1.50-1.40 (t, 3H)37 7 TFA salt 434.45 CDCl₃ 13.45-13.20 (bs, 321 1 5.09 1H), 7.40-7.05(m, 8H), 5.0-4.9 (t, 1H), 4.8-4.6 (t, 1H), 4.25- 4.05 (m, 3H), 3.70-3.60 (m, 1H), 3.40- 3.30 (m, 2H), 3.05 (m, 1H)3.00-2.91 (m, 3H), 2.3 (s,3H) 38 8 TFA salt 448.48 CDCl₃ 13.40-13.10 (bs, 335 1 5.29 1H),7.40-7.30 (t, 2H), 7.29-7.10 (m, 6H), 5.07-4.95 (m, 1H), 4.75-4.60 (t,1H), 4.25-4.02 (m, 3H), 3.75-3.65 (m, 1H), 3.40-3.0 (m, 5H), 2.35 (S,3H), 1.47-1.40 (t, 3H) 26 9 TFA salt 405.41 CDCl₃ 13.5 (bs, 1H), 8.7 (d,292 1 3.5 1H), 7.9-7.8 (m, 1H), 7.6-7.5 (m, 1H), 7.40-6.95 (m, 5H),4.80-4.65 (d, 2H), 4.50-4.40 (m, 1H), 4.10-4.0 (d, 1H), 3.80-3.70 (m,1H), 3.40-3.30 (m, 2H), 3.28-3.18 (m, 1H), 3.10 (s, 3H), 2.95 (m, 2H).27 30 Free Base 325.84 CDCl₃ 8.63-5.58 (d, 1H), 326 1 3.9 7.5-7.4 (t,2H), 7.18- 7.1 (m, 4H), 4.42- 4.38 (t, 2H), 3.6 (S, 2H), 3.2-3.17 (t,2H), 2.78-2.7 (t, 2H), 2.65-2.60 (t, 2H), 2.5 (t, 2H) 28 10 TFA salt405.41 CDCl₃ 8.6-8.54 (d, 2H), 292 1 3.5 7.4-7.36 (d, 1H), 7.34-7.29 (d,2H), 7.18-7.13 (m, 2H), 7.06-7.02 (d, 1H), 4.80-4.70 (d, 1H), 4.4 (m,2H), 4.20- 4.05 (d, 1H), 3.95 (m, 1H), 3.30-3.20 (m, 4H), 3.1 (s, 3H),2.78-2.75 (d, 1H) 18 31 TFA salt 447.49 CDCl₃ 8.22 (s, 1H), 7.24- 334 14.13 7.20 (d, 2H), 7.20- 7.18 (d, 1H), 7.05- 6.80 (m, 2H), 4.20- 4.18(t, 2H), 3.70 (s, 2H), 3.0-2.9 (m, 2H), 2.82-2.78 (t, 2H), 2.70-2.60 (t,2H), 2.58-2.50 (bs, 5H), 2.48-2.40 (s, 3H), 1.3 (t, 3H) 31 17 Free Base291.39 CDCl₃ 8.4 (s, 1H), 7.46- 292 1 3.55 7.43 (dd, 1H), 7.23- 7.19(dd, 1H), 7.15- 7.02 (m, 4H), 5.20 (s, 2H), 3.70 (s, 2H), 2.85-2.75 (m,4H), 2.55 (s, 3H), 2.45 (s, 3H) 41 34 Oxalate Salt 412.45 DMSO 7.40-6.90(m, 7H), 323 1 5.77 4.30-4.20 (t, 2H), 3.4 (S, 2H), 3.06-2.95 (t, 2H),2.80 (s, 3H), 2.60-2.4 (m, 4H), 2.40 (s, 3H). 19 32 TFA salt 452.9 CDCl₃7.30-7.08 (m, 5H), 339 1 6.03 6.85-6.78 (d, 2H), 4.70-4.60 (d, 1H),4.40-4.20 (m, 1H), 4.20-4.0 (m, 2H), 3.65-3.50 (m, 1H), 3.10-3.00 (m,3H), 2.85 (s, 3H), 2.80 (m, 1H), 2.45 (s, 3H), 2.2 (m, 1H). 42 163 FreeBase 310.48 CDCl₃ 7.38-7.18 (m, 3H,), 311 1 6.55 4.05-3.98 (m, 2H),3.70-3.60 (t, 2H), 2.88-2.80 (t, 4H), 2.6 (s, 3H), 2.40 (s, 3H,),1.8-0.8 (m, 13H) 43 33 Oxalate Salt 412.45 CD₃OD 7.30-7.25 (d, 1H), 3231 5.78 7.22-7.20 (s, 1H), 7.10-7.0 (d, 1H), 6.9- 6.98 (m, 4H), 4.8-4.2(m, 4H), 3.6-3.2 (m, 2H), 3.0 (t, 2H), 2.98 (S, 3H), 2.65 (bs, 2H)2.4(s, 3H) 44 35 Oxalate Salt 420.5 DMSO 7.39-7.30 (d, 1H), 331 1 5.967.26-7.12 (m, 4H), 7.1-6.9 (d, 3H), 4.4- 4.3 (s, 2H,), 4.3-4.2 (t, 2H),4.0-3.3 (m, 2H), 2.95-2.90 (t, 2H), 2.80-2.60 (m, 2H,), 2.3 (s, 3H),1.75 (S, 1H), 1.0-0.8 (m, 4H) 45 36 TFA salt 438.87 CDCl₃ 7.40-7.35 (d,1H), 325 1 5.73 7.34-7.30 (s, 1H), 7.23-7.15 (m, 4H), 6.92-6.68 (m, 2H),4.6 (d, 1H), 4.4 (m, 1H), 4.20 (m, 1H), 4.0 (d, 1H), 3.60- 3.45 (m, 1H),3.10 (bs, 3H), 2.90 (s, 3H), 2.70-2.60 (m, 1H), 2.10 (m, 1H). 50 216Free Base 333.43 CDCl₃ 8.3 (s, 1H), 8.04 (s, 334 1 4.3 1H), 7.24-7.22(m, 1H), 7.09-7.06 (d, 1H), 6.96-6.93 (d, 1H), 6.81-6.79 (dd, 1H),4.26-4.23 (t, 2H), 3.40-3.30 (t, 2H), 3.09-3.03 (m, 5H), 2.43-2.39 (t,2H), 2.5 (S, 3H), 2.48 (S, 3H) 46 186 Dioxalate Salt 513.93 D₂O 7.55 (s,1H), 7.43- 334 3 4.15 7.40 (t, 1H), 7.30- 7.20 (t, 1H), 4.8-4.2 (m, 4H),4.2-3.8 (m, 4H), 3.6-3.2 (m, 10H), 3.05 (s, 3H). 47 164 Oxalate Salt420.93 DMSO 7.55 (s, 1H), 7.50- 331 3 7.33 7.40 (d, 1H), 7.20- 7.10 (d,1H), 4.30 (t, 2H), 4.20-4.10 (t, 2H), 3.50 (t, 2H), 3.10 (s, 2H), 2.90(s, 3H), 1.8-0.8 (m, 13H). 48 187 Oxalate Salt 420.93 DMSO 7.40 (d, 1H),7.12 (t, 331 3 7.28 1H), 7.02 (d, 1H), 4.70 (s, 2H), 4.20- 4.10 (t, 2H),3.60- 3.50 (d, 2H), 3.20- 3.08 (d, 2H), 2.90 (s, 3H), 1.8-0.8 (m, 13H).48 188 Oxalate Salt 420 DMSO 7.60 (s, 1H), 7.50- 331 3 8.38 7.40 (d,1H), 7.10- 7.0 (d, 1H), 4.20 (t, 2H), 3.6 (bs, 2H), 3.10-3.0 (d, 2H),2.90-2.80 (d, 2H), 2.60-2.50 (s, 3H), 1.8-0.8 (m, 13H). 49 221 DioxalateSalt 477.21 D₂O 7.50-7.45 (d, 1H), 298 3 3.99 7.40 (s, 1H), 7.30- 7.20(d, 1H), 4.80- 4.70 (d, 1H), 4.60- 4.50 (d, 2H), 4.40- 4.30 (d, 1H),4.0- 3.90 (d, 1H), 3.70- 3.60 (m, 6H), 3.30- 3.20 (m, 1H), 3.19 (s,3H)3.05 (m, 2H), 2.42 (s, 3H), 2.20- 2.11 (d, 2H), 2.10- 1.90 (d, 2H) 50215 Free Base 334.41 CDCl₃/ 7.55-7.50 (m, 2H), 305 (M- 1 6.54 D₂O7.18-7.0 (m, 6H), CHO) 6.22-6.17 (d, 1H), 4.5 (s, 2H), 4.42- 4.36 (t,2H), 3.2-3.0 (m, 5H), 2.5 (s, 3H) 52 224 Dioxalate Salt 491.5459 D₂O7.45 (d, 1H), 7.4 (s, 312 3 4.11 1H), 7.2 (d, 1H), 4.6 (bs, 2H), 4.4 (d,1H), 3.9 (m, 1H), 3.6 (m, 4H), 3.45 (t, 2H), 3.4-3.2 (m, 2H), 3.15 (s,3H), 3.05 (t, 2H), 2.45 (s, 3H), 2.05- 1.4 (m, 6H). 53 225 TFA Salt453.89 CDCl₃ FREE BASE 8.2 (s, 340 3 4.25 1H), 7.4 (s, 1H), 7.1- 6.9 (m,6H), 4.2 (t, 2H), 3.6 (s, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 2.5 (s, 6H),2.6-2.4 (m, 2H) 54 226 TFA Salt 568.63 CDCl₃ 8.15 (s, 1H), 7.4-7.0 455 35.89 (m, 5H), 4.8-2.6 (m, 15H), 3.05 and 3.0 (s, 3H), 2.55 and 2.4 (s,3H), 2.0-1.8 (m, 4H), 1.4 (s, 9H) 55 227 Free Base 465.83 CDCl₃ 7.4-7.2(m, 5H), 7.05 465 3 10.46 (d, 1H), 7.0-6.9 (m, 2H), 4.85-4.7 (2H), 4.2(t, 2H), 3.7 (m, 2H), 3.5 (m, 1H), 3.0 (t, 2H), 2.5 (s, 3H), 2.4-2.2 (m,2H), 1.8 (m, 1H) 56 228 Free Base 290.4 CDCl₃ 8.4 (s, 1H), 7.4-7.2 291 36.33 (m, 5H), 7.05 (d, 1H), 6.9 (m, 2H), 4.2 (m, 4H), 3.2 (t, 2H), 3.0(t, 2H), 2.45 (s, 3H), 2.4 (m, 2H) 57 229 Free Base 335.44 CDCl3 8.4 (s,1H), 7.45 (d, 336 3 4.01 1H), 7.4 (s, 1H), 7.3 (d, 1H), 7.1 (d, 1H),6.65 (d, 1H), 3.7 (m, 2H), 3.2 (m, 1H), 2.95 (t, 2H), 2.8 (m, 1H), 2.55(s, 3H), 2.5 (t, 2H), 2.4 (bs, 2H), 2.3 (s, 3H), 2.05 (s, 3H) 58 230Oxalate Salt 467.57001 DMSO 9.2 (bs, 1H), 8.2 (s, 306 3 4.06 1H), 7.5(d, 1H), 7.4 (d, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 6.95 (s, 1H), 4.25 (m,4H), 3.4 (m, 2H), 3.0-2.8 (m, 4H), 2.4 (s, 3H), 2.35 (s, 3H). 59 231 TFASalt 468.52372 DMSO 10.05 (bs, 1H), 7.9 355 3 3.98 (bs, 2H), 7.35 (d,1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.6-4.2 (m, 6H), 3.9-3.7 (m, 2H), 3.6-3.3(m, 4H), 3.2 (m, 2H), 3.0 (s, 3H), 2.8 (m, 1H), 2.6-2.4 (m, 2H), 2.4 (s,1H), 1.85 (m, 2H), 1.4-1.2 (m, 2H). 60 232 TFA Salt 526.35726 CDCl₃ 4123 5.08 61 233 DiHCl Salt 392.37544 DMSO 8.5 (d, 1H), 8.1 (t, 320 3 4.141H), 7.65-7.5 (d, 2H), 7.3 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.5 (d,1H), 4.2 (d, 1H), 4.1 (t, 2H), 3.1 (m, 2H), 3.0 (s, 3H), 2.9 (t, 2H),2.6-2.4 (m, 2H), 2.35 (s, 3H), 2.1 (quint 2H) 62 234 TFA Salt 548.32287CDCl₃ 7.7 (s, 1H), 7.5 (d, 435 3 5.08 1H), 7.25 (m, 1H), 7.1 (d, 1H),7.05 (t, 1H), 6.95 (t, 1H), 6.7 (t, 1H), 4.6 (d, 1H), 4.25 (m, 2H), 4.0(d, 1H), 3.65 (m, 1H), 3.1 (m, 1H), 3.05 (m, 2H), 2.9 (m, 1H), 2.85 (s,3H), 2.5 (m, 1H) 67 236 TFA Salt 459.9 CDC13 7.35 (s, 1H), 7.2 (d, 346 15.57 1H), 7.1 (d, 1H), 4.9 (d, 1H), 4.65 (m, 2H), 4.1 (d, 1H), 3.8 (m,1H), 3.5 (dt, 4H), 3.4-3.2 (m, 2H), 3.0 (s, 3H), 3.0-2.95 (m, 1H),1.8-1.5 (m, 6H). 68 237 Free Base 359.89 CDC13 7.4 (s, 1H), 7.15 (s, 3601 5.94 2H), 4.75 (s, 2H), 4.5 (d, 1H), 3.8 (m, 1H), 3.65 (m, 2H), 3.05(m, 1H), 2.9-2.7 (m, 4H), 2.6 (m, 1H), 2.5 (s, 3H), 1.8-1.0 (m, 5H),0.95 (d, 3H). 69 238 Oxalate Salt 437.88 DMSO 7.5 (s, 1H), 7.35 (d, 3481 4.87 1H), 7.1 (d, 1H), 5.05 (s, 2H), 4.35 (s, 2H), 3.75 (t, 2H), 3.65(m, 1H), 3.65 (m, 5H), 3.4 (m, 1H), 3.05 (t, 2H), 2.95 (m, 1H), 2.9 (s,3H). 70 239 Oxalate Salt 453.94 DMSO 7.5 (s, 1H), 7.45 (d, 364 1 5.421H), 7.1 (d, 1H), 5.15 (s, 2H), 4.3 (s, 2H), 3.8 (m, 2H), 3.6 (m, 1H),3.6-3.4 (m, 2H), 2.95 (bs, 2H), 2.9 (s, 3H), 2.75 (bs, 2H), 2.6 (bs,2H). ²Method-1 Column: YMC ODS-A 150 mm × 4.6 mm × 5μ , ID:E-AC-1/06/COL/013 Mobile Phase: A: 0.05% TFA in Water/B: 0.05% TFA inAcetonitrile Inj. Vol: 10 μL, Col. Temp.: 30° C., Flow rate: 1.2 mL/minGradient: 10% B to 80% B in 5 min, Hold for 2 min, 7.01-10 min 10% BMethod-2 Column: YMC ODS-A 150 mm × 4.6 mm × 5μ , ID: E-AC-1/06/COL/013Mobile Phase: A: 0.05% TFA in Water/B: 0.05% TFA in Acetonitrile Inj.Vol: 10 μL, Col. Temp.: 30° C., Flow rate: 1.2 mL/min Gradient: 50% B to100% B in 5 min, Hold for 2 min, 7.01-10 min 50% B Method-3 Column: YMCODS-A 150 mm × 4.6 mm × 5μ, ID: E-AC-1/06/COL/013 Mobile Phase: A: 0.05%TFA in Water/B: 0.05% TFA in Acetonitrile Inj. Vol: 10 μL , Col. Temp.:30° C., Flow rate: 1.4 mL/min Gradient: 5% B to 95% B in 8 min, Hold for1.5 min, 9.51-12 min 5% B

Example 60 Determination of the Ability of Compounds of the Invention toBind a Histamine Receptor

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H1 receptor expressed inChinese hamster ovary (CHO) cells (De Backer M D et al. Biochem.Biophys. Res Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) were used.Compounds of invention were incubated with 1.2 nM [³H]Pyrilamine for 180minutes at 25° C. Non-specific binding was estimated in the presence of1 μM pyrilamine. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Pyrilamine specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 5.

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H2 receptor expressed inChinese hamster ovary (CHO) K1 cells (Ruat M. Proc Natl Acad Sci USA.87(5):1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 were used.Compounds of invention were incubated with 0.1 nM [¹²⁵I]Aminopotentidinefor 120 minutes at 25° C. Non-specific binding was estimated in thepresence of 3 μM Tiotidine. Receptor proteins were filtered and washed,the filters were then counted to determine [¹²⁵I]Aminopotentidinespecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 5.

TABLE 5 Binding data. Example Compd. Histamine Binding No. No. H1 H2 925 97 (1 μM) 96 (1 μM) 89 (0.1 μM) 75 (0.3 μM) 71 (0.03 μM) 54 (0.1 μM)10 18 −14 (1 μM) 1 (1 μM) 39 19 −3 (1 μM) 10 (1 μM) 11 24 −4 (1 μM) 13(1 μM) 40 20 97 (1 μM) 72 (1 μM) 93 (0.1 μM) 51 (0.3 μM) 73 (0.02 μM) 33(0.1 μM) 34 (4 nM) 29 139 Lot 1: 81 (1 μM) Lot 1: 18 (1 μM) Lot 2: 74 (1μM) Lot 2: 7 (1 μM)  20 21 79 (1 μM) 45 (1 μM) 21 22 100 (1 μM) 49 (1μM) 91 (0.3 μM) 29 (0.3 μM) 63 (0.03 μM) 36 (10 nM) 22 23 69 (1 μM) 28(1 μM) 12 37 101 (1 μM) 53 (1 μM) 78 (0.1 μM) 22 (0.3 μM) 59 (0.03 μM)13 26 96 (1 μM) 73 (1 μM) 81 (0.1 μM) 34 (0.3 μM) 67 (0.03 μM) 23 27 99(1 μM) 32 (1 μM) 77 (0.1 μM) 58 (0.03 μM) 14 1 91 (1 μM) 82 (1 μM) 56(0.1 μM) 57 (0.3 μM) 32 (0.03 μM) 33 (0.1 μM) 15 2 87 (1 μM) 81 (1 μM)54 (0.1 μM) 56 (0.3 μM) 31 (0.03 μM) 34 (0.1 μM) 32 137 11 (1 μM) 45 (1μM) 30 138 68 (1 μM) 27 (1 μM) 33 140 15 (1 μM) 45 (1 μM) 16 4 93 (1 μM)51 (1 μM) 73 (0.1 μM) 34 (0.3 μM) 47 (0.03 μM) 17 3 88 (1 μM) 51 (1 μM)24 5 82 (1 μM) 2 (1 μM) 25 6 32 (1 μM) −3 (1 μM) 35 28 81 (1 μM) 58 (1μM) 40 (0.3 μM) 36 29 100 (1 μM) 59 (1 μM) 57 (0.1 μM) 27 (0.3 μM) 37(0.03 μM) 34 16 10 (1 μM) 3 (1 μM) 37 7 47 (1 μM) 58 (1 μM) 38 8 54 (1μM) 26 (1 μM) 26 9 18 (1 μM) 16 (1 μM) 27 30 80 (1 μM) 34 (1 μM) 28 1088 (1 μM) 12 (1 μM) 18 31 100 (1 μM) 34 (1 μM) 31 17 15 (1 μM) −2 (1 μM)41 34 96 (1 μM) 89 (1 μM) 67 (0.1 μM) 22 (10 nM) 19 32 101 (1 μM) 101 (1μM) 87 (0.1 μM) 99 (0.3 μM) 52 (10 nM) 42 163 103 (1 μM) 88 (1 μM) 92(0.1 μM) 59 (10 nM) 43 33 98 (1 μM) 91 (1 μM) 89 (0.1 μM) 41 (0.1 μM) 46(10 nM) 44 35 99 (1 μM) 54 (1 μM) 45 36 99 (1 μM) 92 (1 μM) 91 (0.1 μM)41 (0.1 μM) 48 (10 nM) 216 6 (1 μM) 11 (1 μM) 12 217 −4 (1 μM) 13 (1 μM)31 218 80 (1 μM) 34 (1 μM) 63 220 3 (1 μM) 22 (1 μM) 64 219 89 (1 μM) 71(1 μM) 57 221 78 (1 μM) 52 (1 μM) 65 222 103 (1 μM) 98 (1 μM) 101 (0.1μM) 89 (0.1 μM) 85 (0.01 μM) 66 223 100 (1 μM) 94 (1 μM) 54 226 87 (1μM) 96 (1 μM) 72 231 −11 (1 μM) 4 (1 μM) 58 230 46 (1 μM) 6 (1 μM) 60232 −6 (1 μM) 3 (1 μM) 233 99 (1 μM) 45 (1 μM) 62 89 97 (1 μM) 88 (1 μM)76 241 19 (1 μM) 11 (1 μM) 67 236 42 (1 μM) 17 (1 μM) 68 237 77 (1 μM)24 (1 μM) 77 242 94 (1 μM) 87 (1 μM) 69 238 26 (1 μM) 6 (1 μM) 70 239 50(1 μM) 10 (1 μM) 71 240 60 (1 μM) 23 (1 μM) 78 243 84 (1 μM) 17 (1 μM)79 244 15 (1 μM) 10 (1 μM) 80 245 22 (1 μM) 8 (1 μM) 81 246 18 (1 μM) 16(1 μM) 82 247 100 (1 μM) 97 (1 μM) 90 255 71 (1 μM) −15 (1 μM) 91 256 −1(2.5 μM) −16 (2.5 μM)

Example 1B Determination of the Ability of Compounds of the Invention toBind an Adrenergic Receptor

Adrenergic α_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1A) receptor obtained from Wistar Ratsubmaxillary glands (Michel, A. D. et al., Br. J. Pharmacol. 98:883,1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) was used. Compounds of the invention were incubated with 0.25nM [³H]Prozosin for 60 minutes at 25° C. Non-specific binding wasestimated in the presence of 10 μM phentolamine. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]Prozosin specifically bound. Compounds of the invention werescreened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of theinvention were tested in this biochemical assay and percent inhibitionof specific binding was determined. Certain compounds showed inhibitionof specific binding by at least about 80%.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver (Garcia-S'ainz, J. A. et al., Biochem. Biophys. Res. Commun.186:760, 1992; Michel A. D. et al., Br. J. Pharmacol. 98:883, 1989) in amodified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA)was used. Compounds of the invention were incubated with 0.25 nM[³H]Prozosin for 60 minutes at 25° C. Non-specific binding was estimatedin the presence of 10 μM phentolamine. Receptor proteins were filteredand washed, the filters were then counted to determine [³H]Prozosinspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay and percent inhibition of specific binding wasdetermined. Certain compounds showed inhibition of specific binding byat least about 80%.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells (Kenny, B. A. et al. Br. J.Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds of invention were incubated with 0.6 nM [³H]Prozosin for60 minutes at 25° C. Non-specific binding was estimated in the presenceof 10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prozosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 6.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2A) receptor expressed ininsect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994)in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2mM EDTA) was used. Compounds of invention were incubated with 1 nM[³H]MK-912 for 60 minutes at 25° C. MK912 is(2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-onehydrochloride Non-specific binding was estimated in the presence of 10μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemicalassay results are presented as the percent inhibition of specificbinding in Table 6.

Adrenergic α_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO-K1) cells (Uhlen S et al. Eur J Pharmacol.343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4,12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used. Compounds of the inventionwere incubated with 2.5 nM [³H]Rauwolscine for 60 minutes at 25° C.Non-specific binding was estimated in the presence of 10 μM Prozosin.Receptor proteins were filtered and washed, the filters were thencounted to determine [³H]Rauwolscine specifically bound. Compounds werescreened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assayresults are presented as the percent inhibition of specific binding inTable 6.

Adrenergic α_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2C) receptor expressed ininsect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994)in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2mM EDTA) was used. Compounds of the invention were incubated with 1 nM[³H]MK-912 for 60 minutes at 25° C. Non-specific binding was estimatedin the presence of 10 μM WB-4101. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]MK-912specifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay and percent inhibition of specific binding wasdetermined. Certain compounds showed inhibition of specific binding byat least about 80%.

Example 2B Determination of the Ability of Compounds of the Invention toBind a Dopamine Receptor

Dopamine D_(2L)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant dopamine D_(2L) receptor expressed inChinese hamster ovary (CHO) cells (Grandy, D. K. et al. Proc. Natl.Acad. Sci. USA. 86:9762, 1989; Hayes, G. et al., Mol. Endocrinol. 6:920,1992) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mMAscorbic Acid, 0.001% BSA, 150 mM NaCl) was used. Compounds of theinvention were incubated with 0.16 nM [³H]Spiperone for 120 minutes at25° C. Non-specific binding was estimated in the presence of 10 μMHaloperidol. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Spiperone specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 6.

Example 3B Determination of the Ability of Compounds of the Invention toBind a Serotonin Receptor

Serotonin (5-Hydroxytryptamine) 5-HT_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(1A) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Martin G R and Humphrey P P A. Neuropharmacol. 33:261, 1994; May J A,et al. J Pharmacol Exp Ther. 306(1): 301, 2003) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mMMgSO₄) was used. Compounds of invention were incubated with 1.5 nM[³H]8-OH-DPAT for 60 minutes at 25° C. Non-specific binding wasestimated in the presence of 10 μM Metergoline. Receptor proteins werefiltered and washed, the filters were then counted to determine [³H]8-OH-DPAT specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay and percent inhibition of specific binding wasdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT_(1B) receptor fromWistar Rat cerebral cortex (Hoyer et al. Eur J Pharmaco. 118: 1, 1985;Pazos et al. Eur J Pharmacol. 106: 531, 1985) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μM Pargyline, 30 μMIsoprenaline) was used. Compounds of invention were incubated with 10 pM[¹²⁵I]Cyanopindolol for 90 minutes at 37° C. Non-specific binding wasestimated in the presence of 10 μM Seretonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[¹²⁵I]Cyanopindolol specifically bound. Compounds were screened at 1 μMor lower, using 1% DMSO as vehicle. Compounds of the invention weretested in this biochemical assay and percent inhibition of specificbinding was determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2A) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Bonhaus, D. W. et al. Br. J. Pharmacol. 115:622, 1995; Saucier, C. andAlbert, P. R., J. Neurochem. 68:1998, 1997) in a 50 mM Tris-HCl buffer,pH 7.4, was used. Compounds of the invention were incubated with 0.5 nM[³H]Ketanserin for 60 minutes at 25° C. Non-specific binding wasestimated in the presence of 1 μM Mianserin. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]Ketanserin specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Biochemical assay results are presentedas the percent inhibition of specific binding in Table 6.

Serotonin (5-Hydroxytryptamine) 5-HT_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2B) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Bonhaus, D. W. et al., Br. J. Pharmacol. 115:622, 1995) in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl₂, 0.1% Ascorbic Acid)was used. Compounds of invention were incubated with 1.2 nM [³H]Lysergicacid diethylamide (LSD) for 60 minutes at 37° C. Non-specific bindingwas estimated in the presence of 10 μM Serotonin (5-HT). Receptorproteins were filtered and washed, the filters were then counted todetermine [³H]LSD specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention were testedin this biochemical assay and percent inhibition of specific binding wasdetermined. Certain compounds showed inhibition of specific binding byat least about 80%.

Serotonin (5-Hydroxytryptamine) 5-HT_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2C) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Wolf, W. A. and Schutz, J. S., J. Neurochem. 69:1449, 1997) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10μM Pargyline) was used. Compounds of the invention were incubated with 1nM [³H]Mesulergine for 60 minutes at 25° C. Non-specific binding wasestimated in the presence of 1 μM Mianserin. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]Mesulergine specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Biochemical assay results are presentedas the percent inhibition of specific binding in Table 6.

Serotonin (5-Hydroxytryptamine) 5-HT₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₃receptor expressed in human embryonic kidney (HEK-293) cells (Miller Ket al. Synapase. 11:58, 1992; Boess F G et al. Neuropharmacology.36:637, 1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1mM EDTA, 5 mM MgCl₂) was used. Compounds of invention were incubatedwith 0.69 nM [³H]GR-65630 for 60 minutes at 25° C. Non-specific bindingwas estimated in the presence of 10 μM MDL-72222. Receptor proteins werefiltered and washed, the filters were then counted to determine[³]GR-65630 specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention were testedin this biochemical assay and percent inhibition of specific binding wasdetermined. Certain compounds showed inhibition of specific binding byat least about 80%.

Serotonin (5-Hydroxytryptamine) 5-HT₄

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT₄ receptor fromDuncan Hartley derived Guinea pig striatum (Grossman C T et al. Br JPharmacol. 109:618, 1993) in a 50 mM Tris-HCl, pH 7.4, was used.Compounds of invention were incubated with 0.7 nM [³H]GR-113808 for 30minutes at 25° C. Non-specific binding was estimated in the presence of30 μM Seretonin (5-HT). Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]GR-113808 specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention were tested in this biochemical assay andpercent inhibition of specific binding was determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(5A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(5A) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Rees, S. et al., FEBS Lett. 355:242, 1994) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used.Compounds of the invention were incubated with 1.7 nM [³H]Lysergic aciddiethylamide (LSD) for 60 minutes at 37° C. Non-specific binding wasestimated in the presence of 100 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[³H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay and percent inhibition of specific binding wasdetermined. Certain compounds showed inhibition of specific binding byat least about 80%.

Serotonin (5-Hydroxytryptamine) 5-HT₆

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT6receptor expressed in human HeLa cells (Monsma, F. J. Jr. et al., Mol.Pharmacol. 43:320, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl,pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used. Compoundsof the invention were incubated with 1.5 nM [3H]Lysergic aciddiethylamide (LSD) for 120 minutes at 37° C. Non-specific binding wasestimated in the presence of 5 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[3H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 6.

Serotonin (5-Hydroxytryptamine) 5-HT₇

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(S) receptor expressed in Chinese hamster ovary (CHO) cells (Roth,B. L. et al., J. Pharmacol. Exp. Ther. 268:1403, 1994; Shen, Y. et al.,J. Biol. Chem. 268:18200, 1993) in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used. Compounds ofinvention were incubated with 5.5 nM [³H] Lysergic acid diethylamide(LSD) for 2 hours at 25° C. Non-specific binding was estimated in thepresence of 10 μM Serotonin (5-HT). Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]LSD specificallybound. Compounds were screened at 1 μM or lower, using 1% DMSO asvehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 6.

Example 4B Determination of the Ability of Compounds of the Invention toBind a Imidazoline I₂ Receptor

Central Imidazoline I₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat central imidazoline I₂ receptor obtained from WistarRat cerebral cortex (Brown, C. M. et al., Br. J. Pharmacol. 99:803,1990) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) was used. Compounds of the invention were incubated with 2 nM[³H]Idazoxan for 30 minutes at 25° C. Non-specific binding was estimatedin the presence of 1 μM Idazoxan. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Idazoxanspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay and percent inhibition of specific binding wasdetermined. Certain compounds showed inhibition of specific binding byat least about 80%.

Example 5B Determination of the Ability of Compounds of the Invention toBind a Histamine Receptor

Histamine H1

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H1 receptor expressed inChinese hamster ovary (CHO) cells (De Backer, M. D. et al., Biochem.Biophys. Res. Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) was used.Compounds of the invention were incubated with 1.2 nM [³H]Pyrilamine for180 minutes at 25° C. Non-specific binding was estimated in the presenceof 1 μM pyrilamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Pyrilamine specificallybound. Compounds were screened at 1 μM, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 6.

Histamine H2

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H2 receptor expressed inChinese hamster ovary (CHO) K1 cells (Ruat, M., Proc. Natl. Acad. Sci.USA. 87(5):1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 was used.Compounds of the invention were incubated with 0.1 nM[¹²⁵I]Aminopotentidine for 120 minutes at 25° C. Non-specific bindingwas estimated in the presence of 3 μM Tiotidine. Receptor proteins werefiltered and washed, the filters were then counted to determine[¹²⁵I]Aminopotentidine specifically bound. Compounds were screened at 1μM, using 1% DMSO as vehicle. Biochemical assay results are presented asthe percent inhibition of specific binding in Table 6.

Histamine H3

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₃ receptor expressed inChinese hamster ovary (CHO-K1) cells (Yanai K et al. Jpn J Pharmacol.65(2): 107, 1994; Zhu Y et al. Mol Pharmacol. 59(3): 434, 2001) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 0.04% BSA)was used. Compounds of invention were incubated with 3 nM[³H]R(−)-α-Methylhistamine for 90 minutes at 25° C. Non-specific bindingwas estimated in the presence of 1 μM R(−)-α-Methylhistamine. Receptorproteins were filtered and washed, the filters were then counted todetermine [³H]R(−)-α-Methylhistamine specifically bound. Compounds werescreened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of theinvention were tested in this biochemical assay and percent inhibitionof specific binding was determined. Certain compounds showed inhibitionof binding by at least about 80%.

TABLE 6 Inhibition of ligand binding to aminergic G protein- coupledreceptors by compounds of the invention: Cmpd Adren. Adren. Adren. Dop.Hist. Hist. Ser. Ser. Ser. Ser. No. alpha1D alpha2A alpha2B D2L H1 H25-HT2A 5-HT2C 5-HT6 5-HT7 Dimebon 91 91 112 41 94 83 82 86 95 1 76 99 6291 82 95 95 87 98 2 72 94 70 87 81 96 97 95 100 3 48 86 102 88 51 98 8240 81 4 56 82 106 93 51 102  94 82 88 5 21 20 78 82 2 55 9 1 37 6 6 2054 32 −3 74 34 7 39 7 55 93 114 47 58 100  82 49 87 8 35 65 94 54 26 8036 9 42 10 19 33 92 88 12 69 53 32 73 16 12 10 10 10 3 14 5 6 14 17 −756 9 15 −2 −7 8 0 7 18 −10 −10 −8 −7 −14 1  5 −14 6 10 19 −6 −8 −8 −5 −310  2 −17 −5 12 20 94 98 108 87 97 87 98 98 104 21 76 82 114 79 45 94 8779 97 22 83 72 105 27 100 53 81 87 91 99 23 61 57 97 69 28 78 53 47 9424 6 7 −1 3 −4 13 −2 1 −4 −2 25 98 99 108 94 97 96 93 99 103 26 92 99105 78 96 73 97 93 94 102 27 63 53 100 99 32 63 29 38 28 89 100 108 6585 84 100  100 99 98 29 89 91 118 100 59 102  84 83 91 30 68 84 102 2980 34 91 90 90 99 31 70 66 91 100 34 65 39 64 85 32 94 97 110 82 101 10196 100 101 101 32 94 97 110 82 101 101 96 100 101 101 33 88 98 100 88 9891 97 95 100 91 34 76 99 107 88 96 89 99 96 104 97 36 87 97 104 92 99 9298 94 104 99 37 81 96 102 61 101 53 92 90 91 98 43 98 100 108 110 100 99100 102 92 45 92 100 102 103 98 100  97 103 99 47 81 98 101 81 78 92 8999 92 51 22 26 10 94 17  0 2 6 17 53 13 18 34 43 4 −1 12 18 49 55 84 8690 29 101 62 86 87 94 56 91 95 119 62 100 76 92 87 102 91 60 82 84 95 24101 56 84 90 91 62 51 51 90 −3 93 15 85 88 83 68 98 94 111 29 99 49 9878 88 103 80 75 98 105 89 71 88 90 101 92 81 47 96 90 94 57 99 98 86 8982 64 99 99 99 99 99 95 103 100 83 92 100 96 97 97 100  99 106 95 89 8298 116 97 88 90 97 103 100 110 61 89 109 35 65 94 99 95 94 92 119 82 81106 7 33 48 84 81 39 137 12 15 3 11 45 −2 10 12 15 138 33 31 19 68 27 145 22 23 139 25 50 52 74 7  2 0 39 74 140 14 17 −4 15 45 −3 −10 8 2 16290 99 112 100 94 98 94 99 94 163 49 93 104 36 103 88 92 99 99 95 164 3295 93 101 84 91 95 99 92 186 41 51 79 97 25 84 89 83 57 187 15 90 57 6469 84 77 53 77 188 8 80 65 97 72 58 66 67 41 189 28 76 72 0 94 87 85 66195 15 4 7 3 22 −4 −5 8 2 215 −5 23 −4 −2 16 −6 2 8 10 216 −7 15 3 6 1112 −11 −8 18 221 30 37 26 78 52 46 69 29 36 224 22 57 46 56 79 32 74 4361 225 86 91 107 32 101 72 92 91 81 227 11 0 0 −5 1 −2 4 9 −8 228 76 87101 81 15 77 82 89 95 230 75 56 104 93 30 33 36 45 231 21 29 11 −11 4  549 3 0 232 5 2 8 −6 3 −10  2 −7 6 233 49 90 96 99 45 92 93 95 101 236 100 9 1 42 17 54 18 237 14 26 12 −1 77 24 36 20 238 2 −13 14 −1 26 6 20 5239 3 0 24 −1 50 10 65 8 240 42 36 50 9 60 23 27 25 243 8 3 6 8 84 17 3312 244 12 22 13 6 15 10 22 13 245 1 8 19 4 22 8 20 −2 246 12 21 11 1 1816 59 2 247 95 99 103 87 100 97  22^(a) 93 107 248 26 27 75 2 85 7 59 67249 65 97 109 64 100 88 98 101 250 93 91 108 21 102 54 101  79 84 93 25114 2 8 −7 55 21 23 7 253 81 93 104 96 97 73 93 105 87 255 2 −8 4 71 −15 1 11 2 11 256 −10 −7 4 −1 −6  2 0 2 257 3 −4 20 −7 64 1 47 2 262 3 8 −281 −8  6 6 −4 6 263 39 34 105 −4 95 15 24 31 31 266 45 83 100 8 93 47 7367 59 267 92 49 100 21 96 42 73 76 69 274 −16 7 9 1 −2  6 −5 −2 −3 27587 29 92 4 92 20 39 31 56 295 4 26 18 −7 −3 10  0 −19 −1 296 3 1 −8 3 36−4 11 2 3 297 15 −2 7 0 43 3 11 9 321 4 12 25 −1 50 25 61 15 322 66 44115 5 89 20 64 69 75 323 49 6 62 8 93 17 16 20 69 324 53 60 98 28 101 6386 57 93 325 36 58 58 −3 90 22 53 50 41 326 40 55 52 −5 47 12 27 31 26328 23 45 21 6 56 4 46 29 29 329 4 37 68 18 16 70 54 15 78 330 8 1 6 −88 6 14 17 19 331 63 50 105 20 102 73 93 72 100 333 96 98 105 74 94 92100  87 100 97 334 110 101 111 76 99 91 101  97 101 335 91 31 104 44 9677 97 72 9 336 98 96 103 82 107 101 96 99 104 337 97 97 117 81 99 92101  94 104 338 83 99 104 22 96 78 94 68 66 341 −3 36 −1 8 28 15 39 1617 342 91 94 108 29 80 39 74 73 72 343 61 90 117 −7 98 29 89 69 57 349100 96 111 86 111 94 97 98 101 100 351 61 8 43 7 74 −2  1 26 −4 353 11 811 5 10 −2 −1 −15 0 357 89 91 106 47 101 68 69 67 85 358 95 96 109 38 9447 95 78 65 359 95 77 90 51 99 94 96 91 95 360 96 101 115 37 101 75 9783 91 91 361 87 30 94 31 106 25 60 58 76 362 76 14 82 17 98 19 27 40 61363 73 59 104 24 95 31 75 66 83 364 77 65 109 29 87 13 59 81 70 369 5125 105 1 39 6 10 57 23 370 71 35 87 10 85 18 15 40 64 371 88 89 98 40 9974 93 87 88 372 94 100 110 44 101 82 96 77 88 94 380 73 78 103 −5 68 6988 70 39 387 47 12 95 1 97 11 54 76 79 392 88 89 109 24 98 58 53 82 61393 16 98 28 28 3 19 26 3 8 394 9 15 19 30 −2  3 −8 5 7 395 9 4 2 2 20 416 50 0 24 396 −20 22 7 12 −11 26 26 40 46 397 19 16 40 5 77 32 50 44 −9398 17 23 50 8 76 24 85 69 15 399 6 16 11 0 42 10  8 73 −5 401 1 3 3 −1236 14 17 39 1 402 −8 7 −17 −12 10 3 −2 8 −13 403 19 30 46 2 54 10 32 350 404 81 94 95 35 102 88 88 78 94 417 1 28 −1 −12 10 19 23 29 5 424 5728 94 17 104 19 52 76 82 425 65 49 99 −1 100 85 84 72 64 426 69 42 98 −799 66 85 80 65 429 69 67 115 23 100 68 76 84 79 443 91 87 117 29 102 9494 95 96 444 91 89 113 32 101 80 95 95 96 449 39 84 104 12 46 51 83 8737 452 82 92 104 52 109 92 97 93 93 96 453 15 39 103 −4 68 5 42 22 31454 43 65 112 4 90 26 68 38 62 455 81 93 120 88 80 91 99 97 99 98 456 96106 110 76 99 98 104  99 98 457 64 85 108 34 91 88 100  93 90 459 0 −9−20 −7 0 −4  1 3 −10 476 95 87 97 30 98 96 100  96 87 481 3 3 19 16 4−17 27 20 14 482 2 −17 10 7 −2 −9 −7 17 4 483 3 −7 12 0 −5 −7  2 9 13484 10 28 30 15 7 −4 39 31 14 485 69 86 98 43 105 71 69 91 94 486 22 4 70 28 11 19 31 14 487 90 88 100 42 98 80 87 84 94 488 84 70 108 22 41 8295 86 68 493 84 74 101 17 46 53 95 95 73 516 26 3 21 −4 49 12  6 58 9C4-1 60 95 94 14 93 47 96 91 51 88 C4-4 92 96 102 46 101 68 100  98 10396 C4-5 56 56 73 18 82 22 89 81 73 66 C4-6 84 96 94 36 100 68 99 94 10590 C4-7 62 86 86 22 98 46 101  90 88 90 C1-1 64 93 110 18 101 57 94 8477 89 C1-5 92 92 113 36 100 73 97 93 101 93 C1-6 72 55 110 29 104 21 8490 84 57 C1-7 66 88 113 25 99 55 96 91 91 90 ^(a)Percent Inhibition at 1nM

Example 6B Determination of Serotonin (5-Hydroxytryptamine) 5-HT_(2A)Agonist/Antagonist of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant serotonin 5-HT_(2A)receptor expressed in human embryonic kidney (HEK-293) cells (Jerman JC, Brough S J, Gager T, Wood M, Coldwell M C, Smart D and Middlemiss DN. Eur J Pharmacol, 414: 23-30, 2001) was used. Cells were suspended inDMEM buffer, and distributed in microplates. A cytoplasmic calciumfluorescent indicator which varies proportionally to the free cytosolicCa²⁺ ion concentration was mixed with probenicid in HBSS buffercomplemented with 20 mM Hepes (pH 7.4), added into each well andequilibrated with the cells for 30 min at 37° C. followed by 30 min at22° C.

To measure agonist effects, compounds of the invention, referenceagonist or HBSS buffer (basal control) is added to the cells and changesin fluorescence intensity are measured using a microplate reader. Forstimulated control measurements, 5-HT at 100 nM is added in separateassay wells.

The results are expressed as a percent of the control response to 100 nM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer was followed by theaddition of 3 nM 5-HT or HBSS buffer (basal control) prior thefluorescence measurements. The results were expressed as a percentinhibition of the control response to 3 nM 5-HT in Table 7. The standardreference antagonist was ketanserin, which was tested in each experimentat several concentrations to generate a concentration-response curvefrom which its IC₅₀ value was calculated. Compounds were screened at 3μM or lower, using DMSO as vehicle.

TABLE 7 Serotonin 5-HT2A Antagonist Assay Serotonin 5HT2A AntagonistAssay Test Concentration % of Control Agonist Response (M) 1st Assay 2ndAssay Mean Cmpd No. 36 3.00E−08 109 108 108.7 Cmpd No. 36 1.00E−07 111102 106.4 Cmpd No. 36 1.00E−07 100 106 103 Cmpd No. 36 1.00E−07 105 115109.9 Cmpd No. 36 3.00E−07 92 105 98.8 Cmpd No. 36 3.00E−07 92 98 94.8Cmpd No. 36 3.00E−07 109 97 102.8 Cmpd No. 36 1.00E−06 21 30 25.4 CmpdNo. 36 1.00E−06 72 69 70.4 Cmpd No. 36 1.00E−06 68 55 61.8 Cmpd No. 363.00E−06 12 −2 5.3 Cmpd No. 36 3.00E−06 −4 23 9.7 Cmpd No. 36 3.00E−06 10 0.4 Cmpd No. 253 3.00E−08 114 119 116.5 Cmpd No. 253 1.00E−07 94 9594.3 Cmpd No. 253 3.00E−07 36 80 57.9 Cmpd No. 253 1.00E−06 0 3 1.5 CmpdNo. 253 3.00E−06 −3 −3 −2.6 Cmpd No. 247 3.00E−08 122 120 121.3 Cmpd No.247 3.00E−08 101 108 104.5 Cmpd No. 247 3.00E−08 103 111 107 Cmpd No.247 1.00E−07 117 116 116.5 Cmpd No. 247 1.00E−07 93 94 93.5 Cmpd No. 2471.00E−07 93 95 93.9 Cmpd No. 247 3.00E−07 87 76 81.7 Cmpd No. 2473.00E−07 49 72 60.6 Cmpd No. 247 3.00E−07 32 38 34.9 Cmpd No. 2471.00E−06 −4 0 −1.7 Cmpd No. 247 1.00E−06 −2 3 0.3 Cmpd No. 247 1.00E−062 0 0.7 Cmpd No. 247 3.00E−06 −4 −3 −3.2

Example 7B Determination of Serotonin (5-Hydroxytryptamine) 5-HT₆Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant 5-HT₆ receptor istransfected in CHO cells (Kohen, R., Metcalf, M. A., Khan, N., Druck,T., Huebner, K., Lachowicz, J. E., Meltzer, H. Y., Sibley, D. R., Roth,B. L. And Hamblin, M. W. Cloning, characterisation and chromosomallocalization of a human 5-HT6 serotonin receptor, J. Neurochem., 66: 47,1996) and the activity of compounds of the invention is determined bymeasuring their effects on cAMP production using the Homogeneous TimeResolved Fluorescence (HTRF) detection method. Cells are suspended inHBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μM IBMX, andthen distributed in microplates and incubated for 45 min at 37° C. inthe absence (control) or presence of compounds of the invention or thereference agonist or antagonist.

For agonist determinations, stimulated control measurement, separateassay wells contain 10 μM 5-HT. Following incubation, the cells arelysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescencedonor (anti-cAMP antibody labeled with europium cryptate) are added.After 60 min at room temperature, the fluorescence transfer is measuredat lex=337 nm and lem=620 and 665 nm using a microplate reader. The cAMPconcentration is determined by dividing the signal measured at 665 nm bythat measured at 620 nm (ratio).

The results are expressed as a percent of the control response to 10 μM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

For antagonist determinations, the reference agonist 5-HT is added at afinal concentration of 100 nM. For basal control measurements, separateassay wells do not contain 5-HT. Following 45 min incubation at 37° C.,the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) andfluorescence donor (anti-cAMP antibody labeled with europium cryptate)are added.

After 60 min at room temperature, the fluorescence transfer is measuredas mentioned above. The results are expressed as a percent inhibition ofthe control response to 100 nM 5-HT. The standard reference antagonistis methiothepin

Example 8B Determination of Dopamine D_(2L) Antagonist Activity ofCompounds

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2L)receptor stably expressed in Chinese hamster ovary (CHO) cells (SenoglesS E et al. J Biol Chem. 265(8): 4507, 1990) was used. Compounds ofinvention were pre-incubated with the membranes (0.1 mg/ml) and 10 mMGDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mMMgCl₂, 1 mM DTT, 1 mM EDTA) for 20 minutes and Scintillation ProximityAssay (SPA) beads were added for another 60 minutes at 30° C. Thereaction was initiated by 0.3 nM [³⁵S]GTPγS for an additional 15 minuteincubation period. Increase of [³⁵S]GTPγS binding by 50 percent or more(350%) relative to the 1 mM dopamine response by compounds of theinvention indicates possible dopamine D_(2L) receptor agonists activity.Inhibition of a 10 μM dopamine-induced increase of [³⁵S]GTPγS bindingresponse by 50 percent or more (350%) by compounds of the inventionindicated receptor antagonist activity. Compounds were screened at 3 μMor lower, using 0.4% DMSO as vehicle. Assay results are presented as thepercent response of specific binding in Table 8.

TABLE 8 Dopamine D_(2L)antagonist activity of compounds of the inventionAntagonist Activity As Measured by % Inhibition D2L 0.03 uM 0.1 uM 0.3uM 1 uM 3 uM Cmpd No. 247 48, 52 66, 81 81, 83 89 91 Cmpd No. 68 not not8 27 54 done done Cmpd No. 253 36, 56 57, 77 81, 89 not not done doneCmpd No. 36 48, 43 73, 57 83, 88 85 104 When two values are listed, this indicates the assay was run twice.

Example 9B Determination of Dopamine D_(2S) Antagonist Activity ofCompounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2S)receptor stably expressed in Chinese hamster ovary (CHO) cells(Gilliland S L and Alper R H. Naunyn-Schmiedeberg's Archives ofPharmacology. 361: 498, 2000) was used. Compounds of invention werepre-incubated with the membranes (0.05 mg/ml) and 3 μM GDP in modifiedHEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1mM EDTA) for 20 minutes and Scintillation Proximity Assay (SPA) beadswere then added for another 60 minutes at 30° C. The reaction wasinitiated by 0.3 nM [³⁵S]GTPγS for an additional 30 minute incubationperiod. Increase of [³⁵S]GTPγS binding by 50 percent or more (350%)relative to the 100 μM dopamine response by compounds of the inventionindicates possible dopamine D_(2S) receptor agonists activity.Inhibition of a 3 μM dopamine-induced increase of [³⁵S]GTPγS bindingresponse by 50 percent or more (350%) by compounds of the inventionindicated receptor antagonist activity. Compounds were screened at 3 μMor lower, using 0.4% DMSO as vehicle. Assay results are presented as thepercent response of specific binding in Table 9.

TABLE 9 Dopamine D_(2S)antagonist activity of compounds of the inventionAntagonist Activity As Measured by % Inhibition D2S 0.03 uM 0.1 uM 0.3uM 1 uM 3 uM Cmpd No. 247 67, 68 97, 89 81, 93  110 108 Cmpd No. 68 notnot 42  70  93 done done Cmpd No. 253 104, 80  94 96 not not done doneCmpd No. 36 76, 85 97 98, 104 102 107When two values are listed, this indicates the assay was run twice.

Example 10B Determination for Agonist or Antagonist Activity ofCompounds of the Invention in a Histamine H1 Functional Assay

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant Histamine H₁ receptorexpressed in human embryonic kidney (HEK-293) cells (Miller, T. R.,Witte, D. G., Ireland, L. M., Kang, C. H., Roch, J. M., Masters, J. N.,Esbenshade, T. A And Hancock, A. A. J. Biomol. Screen., 4: 249-258,1999) is used. Cells are suspended in DMEM buffer, and then distributedin microplates. A cytoplasmic calcium fluorescent indicator—which variesproportionally to the free cytosolic Ca²⁺ ion concentration—is mixedwith probenicid in HBSS buffer complemented with 20 mM Hepes (pH 7.4)and is then added into each well and equilibrated with the cells for 30min at 37° C. and then for another 30 min at 22° C. To measure agonisteffects, compounds of the invention, reference agonist or HBSS buffer(basal control) are added to the cells and changes in fluorescenceintensity are measured using a microplate reader. For stimulated controlmeasurements, histamine at 10 μM is added in separate assay wells.

The results are expressed as a percent of the control response to 10 μMhistamine. The standard reference agonist is histamine, which is testedin each experiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 300 nM histamine or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as percentinhibition of the control response to 300 nM histamine. The standardreference antagonist is ketanserin, which is tested in each experimentat several concentrations to generate a concentration-response curvefrom which its IC₅₀ value is calculated. Compounds are screened at 3 μMor lower, using DMSO as vehicle.

Example 11B Increase of Neurite Outgrowth of Neurons that were Culturedwith Compounds of the Invention

Neurite Outgrowth in Cortical Neurons

Compounds were tested to determine their ability to stimulate neuriteoutgrowth of cortical neurons. Standard methods were used to isolatecortical neurons. For the isolation of primary rat cortical neurons, thefetal brain from a pregnant rat at 17 days of gestation was prepared inLeibovitz's medium (L15; Gibco). The cortex was dissected out, and themeninges were removed. Trypsin (Gibco) was used to dissociate cortical Cwith DNAse I. The cells were triturated for 30 minutes with a pipette inDulbecco's Modified Eagle Media (“DMEM”; Gibco) with 10% Fetal BovineSerum (“FBS”) (Gibco) and centrifuged at 350×g for 10 minutes at roomtemperature. The cells were suspended in Neurobasal medium supplementedwith 2% B27 (Gibco) and 0.5 mM L-glutamine (Gibco). The cells weremaintained at 30,000 cells per well of poly-L-lysine coated plates at37° C. in 5% CO₂-95% air atmosphere. After adhesion, a vehicle controlor compounds of the invention were added at different concentrations tothe medium. BDNF (50 ng/mL) was used as a positive control for neuritegrowth. After treatment, cultures were washed in phosphate-bufferedsaline (“PBS”; Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cellswere fixed after 3 days growth. Several pictures (˜80) of cells withneurites were taken per condition with a camera. The length measurementswere made by analysis of the pictures using software from Image-Pro Plus(France). The results were expressed as mean (s.e.m.). Statisticalanalysis of the data was performed using one way analysis of variance(ANOVA). Results for compounds 395, 68, 250 and 20 are shown in FIGS.1A-D.

Neurite Outgrowth in Rat Mixed Cortical Cultures

Cortical mixed cultures were prepared from E18 Wistar rat embryos. Thecortices were dissected out and the tissue was cut to small pieces. Thecells were separated by 15-min incubation with DNase and papain. Thecells were collected by centrifugation (1500 rpm, 5 min). The tissue wastriturated with a pipette and the cells were plated using themicro-islet protocol (20 000 cells in 25 μl medium) on poly-L-lysinecoated 48 wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/mlgentamicin, 10% heat-inactivated fetal bovine serum (FBS-HI) and 10%heat-inactivated horse serum (HS-HI). After the cells had attached tothe well, 250 μl medium was added to the wells. Four hours after platingthe medium was changed to fresh medium (MEM with supplements and 5%HS-HI) containing test compound at 0.5, 5 and 50 nM concentrations. Aspositive controls BDNF (50, 100 and/or 150 ng/ml), and/or NGF (50 ng/mland/or 100 ng/ml) were used. After 2 days in vitro, the cell'sconditioned media were collected from plates before fixing the cells.The media samples were centrifuged 13 000 rpm 3 min to get rid of celldebris. The samples were stored at −20 C for later analysis. Cells wereformaldehyde-fixed and processed for immunocytochemistry. BDNF levels inthe conditioned media were determined with a BDNF ELISA using themanufacturers (Promega, BDNF Emax® ImmunoAssay System, catalog number:G7610) instructions.

The cultures were fixed with 4% formaldehyde in 0.01 M PBS for 30 minand washed once with PBS. The fixed cells were first permeabilized andnon-specific binding was blocked by a 30-min incubation with blockingbuffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS.Rabbit anti-MAP-2 (dilution 1:1000, AB5622, Chemicon, in blockingbuffer) was used as a primary antibody. The cells were incubated withthe primary antibody for 48 h at +4° C., washed with PBS and incubatedwith secondary antibody goat anti-rabbit IgG conjugated to AlexaFluor568 (1:200, A11036, Molecular Probes) for 2 h at RT. Theimmunopositive cells were visualized by a fluorescence microscopeequipped with appropriate filter set, and documented by a highresolution image capturing. The number of cells per field (4 field perwell) were counted, and the neurite outgrowth was quantified using ImagePro Plus software.

The number of wells per compound concentration used was 6 (n=6). Alldata are presented as mean±standard deviation (SD) or standard error ofmean (SEM), and differences are considered to be statisticallysignificant at the p<0.05 level. Statistical analysis was performedusing StatsDirect statistical software. Differences between group meanswere analyzed by using 1-way-ANOVA followed by Dunnet's test (comparisonto the vehicle treated group). Results for compound 395 are shown inFIG. 1E.

Example 12B Use of an In Vivo Model to Evaluate the Ability of Compoundsto Enhance Cognition, Learning and Memory in Scopolamine Treated Rats

The two-trial object recognition paradigm developed by Ennaceur andDelacour in the rat was used as a model of episodic memory. Ennaceur,A., and Delacour, J. (1988), Behav. Brain Res. 31:47-59. The paradigm isbased on spontaneous exploratory activity of rodents and does notinvolve rule learning or reinforcement. The object recognition paradigmis sensitive to the effects of ageing and cholinergic dysfunction. See,e.g., Scali, C., et al., (1994), Neurosci. Letts. 170:117-120; andBartolini, L., et al., (1996), Biochem. Behav. 53:277-283.

Male Sprague-Dawley rats between six and seven weeks old, weighingbetween 220-300 grams were obtained from Centre d'Elevage (Rue Janvier,B. P. 55, Le Genest-Saint-Isle 53940, France). The animals were housedin groups of 2 to 4 in polypropylene cages (with a floor area of 1032cm²) under standard conditions: at room temperature (22±2° C.), under a12 hour light/12 hour dark cycle, with food and water provided adlibitum. Animals were permitted to acclimate to environmental conditionsfor at least 5 days before therapy began, and were numbered on theirtails with indelible marker.

The experimental arena was a square wooden box (60 cm×60 cm×40 cm)painted dark blue, with 15 cm×15 cm black squares under a clearplexiglass floor. The arena and objects placed inside the arena werecleaned with water between each trial to eliminate any odor trails leftby rats. The arena was placed in a dark room illuminated only by halogenlamps directed towards the ceiling in order to produce a uniformly dimlight in the box of approximately 60 lux. The day before testing,animals were allowed to freely explore the experimental arena for threeminutes in the presence of two objects (habituation). Animals to betested were placed in the experimental room at least 30 minutes beforetesting.

On the day of the experiment, animals were submitted to two trialsseparated by an interval of 120 minutes. During the first, oracquisition, trial (T₁), rats were placed in the arena, which wasprepared with two identical objects. The time required for each animalto complete 15 seconds of object exploration was determined, with acut-off time of four minutes. Exploration was considered to be directingthe nose at a distance less than 2 centimeters (“cm”) from the objectand/or touching the object. During the second, or testing, trial (T₂),one of the objects presented in the first trial was replaced with anunknown or novel object, while the second, familiar object was left inplace. Rats were placed back in the arena for three minutes, andexploration of both objects was determined. Locomotor activity of rats(number of times rats cross grid lines visible under the clearplexiglass floor) was scored for during T₁ and T₂. At the conclusion ofthe experiments, the rats were sacrificed by an overdose ofpentobarbital given intraperitoneally.

The following parameters were measured: (1) time required to achieve 15seconds of object exploration during T₁; (2) locomotor activity duringT₁ (number of crossed lines); (3) time spent in active exploration ofthe familiar object during T₂ (T_(Familiar)); (4) time spent in activeexploration of the novel object during T₂ (T_(Novel)); and (5) locomotoractivity during T₂ (number of crossed lines). The difference betweentime spent in active exploration of the novel object during T₂ and timespent in active exploration of the familiar object during T₂(ΔT_(Novel)−T_(Familiar)) was evaluated. The % of animals in each groupwith T_(Novel)−T_(Familiar) greater than or equal to 5 seconds was alsoderived; described as % of good learners.

Animals not meeting a minimal level of object exploration were excludedfrom the study as having naturally low levels of spontaneousexploration. Thus, only rats exploring the objects for at least fiveseconds (T_(Novel)+T_(Familiar)>5 seconds) were included in the study.

Animals were randomly assigned to groups of 14. Compounds of theinvention and controls were administered to animals the groups asfollows: Solutions of compounds were prepared freshly each day at aconcentration of 0.25 mg/ml using purified water or saline as vehicle.Donepezil, used as a positive control, and scopolamine were administeredsimultaneously in a single solution of saline (5 mL/kg) prepared freshlyeach day. Scopolamine was purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) was dissolved in saline to aconcentration of 0.06 mg/mL.

Donepezil or its vehicle and scopolamine were administeredintraperitoneally forty minutes before the acquisition trial (T₁).Compounds or their vehicle were administered by gavage twenty-fiveminutes before the acquisition trial (T₁), i.e., five minutes afteradministration of scopolamine. The volume of administration was 5 ml/kgbody weight for compounds administered intraperitoneally, and 10 ml/kgfor compounds administered orally.

Recognition scores and % of good learners for compounds 225, 68 and 395are shown in FIGS. 2 A-F.

Example 13B Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in PCP Treated Animals

In vivo models of schizophrenia can be used to determine the ability ofthe compounds described herein to treat and/or prevent and/or delay theonset and/or the development of schizophrenia.

One exemplary model for testing the activity of one or more compoundsdescribed herein to treat and/or prevent and/or delay the onset and/ordevelopment of schizophrenia employs phencyclidene, which isadministered to the animal (e.g., non-primate (rat) or primate(monkey)), resulting in dysfunctions similar to those seen inschizophrenic humans. See Jentsch et al., 1997, Science 277:953-955 andPiercey et al., 1988, Life Sci. 43(4):375-385). Standard experimentalprotocols may be employed in this or in other animal models. Oneprotocol involves PCP-induced hyperactivity.

Male C57Bl/6J mice from Jackson Laboratories (Bar Harbor, Me.) wereused. Mice were received at 6-weeks of age. Upon receipt, mice wereassigned unique identification numbers (tail marked) and were grouphoused with 4 mice/cage in OPTI mouse ventilated cages. All animalsremained housed in groups of four during the remainder of the study. Allmice were acclimated to the colony room for at least two weeks prior totesting and were subsequently tested at an average age of 8 weeks ofage. During the period of acclimation, mice were examined on a regularbasis, handled, and weighed to assure adequate health and suitability.Animals were maintained on a 12/12 light/dark cycle. The roomtemperature was maintained between 20 and 23° C. with a relativehumidity maintained between 30% and 70%. Food and water were provided adlibitum for the duration of the study. In each test, animals wererandomly assigned across treatment groups.

The open filed (OF) test assesses locomotor behavior. The open fieldchambers are Plexiglas square chambers (27.3×27.3×20.3 cm; MedAssociates Inc., St Albans, Vt.) surrounded by infrared photobeams(16×16×16) to measure horizontal and vertical activity. The analysis wasconfigured to divide the open field into a center and periphery zone.Distance traveled was measured from horizontal beam breaks as the mousemoved whereas rearing activity was measured from vertical beam breaks.

Mice (10 to 12 animals per treatment group) were brought to the activityexperimental room for at least 1 hr acclimation to the experimental roomconditions prior to testing. Eight animals were tested in each run. Micewere administered vehicle (10% DMSO or 5% PEG200 and 1% Tween 80),compound of the invention, clozapine and placed in the OF chambers for30 min following which they were injected with either water or PCP andplaced back in the OF chambers for a 60-minute session. At the end ofeach OF test session the OF chambers were thoroughly cleaned.

Compound 36 in the PCP Hyperactivity Mouse Model of Schizophrenia

Compound 36 (doses tested include: 0.05, 0.15, 0.45, 1.5, 4.5, 15, 30)was dissolved in 5% PEG200, 1% Tween80 and administered orally 30 minprior to PCP injection. Clozapine (1 mg/kg) was dissolved in 10% DMSOand administered i.p. 30 min prior to PCP injection. PCP (5 mg/kg) wasdissolved in sterile injectable water and administered i.p.

Data were analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity wasmeasured during the first 30 min of the test prior to PCP injection.PCP-induced activity was measured during the 60 min following PCPinjection. Statistical outliers that fell above or below 2 standarddeviations from the mean were removed from the final analyses. An effectwas considered significant if p<0.05.

Total distances traveled and total rearing for compound 36 are shown inFIGS. 3A-F.

Compound 247 in the PCP Hyperactivity Mouse Model of Schizophrenia

Protocol was as described above with the exception of the treatmentgroups which were as follows: All injections were at a dose volume of 10ml/kg. The following compounds were used for this study: Compound 247(0.05, 0.15, 0.45, 1.5, 4.5, and 15.0 mg/kg) was dissolved in PhosphateBuffered Saline (PBS) and administered orally 30 min prior to PCPinjection. Clozapine (0.5 and 1.0 mg/kg) was dissolved in 10% DMSO andadministered i.p. 30 min prior to Phencyclidine (PCP) injection. PCP(5.0 mg/kg) was dissolved in sterile injectable water and administeredi.p.

Total distances traveled for compound 247 are shown in FIGS. 4 A-C.

Example 14B Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in Amphetamine Treated Animals

Male C57Bl/6J mice from appropriate supplier (for example JacksonLaboratories, Bar Harbor, Me.) are used. Mice typically are received at6-weeks of age. Mice are acclimated to the colony room for at least twoweeks prior to testing. During the period of acclimation, mice areexamined on a regular basis, handled, and weighed to assure adequatehealth and suitability and maintained on a 12/12 light/dark cycle. Theroom temperature is maintained between 20 and 23° C. with a relativehumidity maintained between 30% and 70%. Food and water are provided adlibitum for the duration of the study. In each test, animals arerandomly assigned between treatment groups.

The open field test (OF) is used to assess motor activity. The openfield chambers are plexiglas square chambers (e.g., 27.3×27.3×20.3 cm;Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeamsources (16×16×16). The enclosure is configured to split the open fieldinto a center and periphery zone and the photocell beams are set tomeasure activity in the center and in the periphery of the OF chambers.Horizontal activity (distance traveled) and vertical activity (rearing)are measured from consecutive beam breaks.

On the day of testing, animals are brought to the experimental room forat least 1 hr acclimation prior to start of treatment. Animals areadministered with vehicle, clozapine or test compound and placed in theOF. The time of administration of client compound to each animal isrecorded. Baseline activity is recorded for 30 min following which micereceive amphetamine (4 mg/kg) or water placed back in the OF chambersfor a 60-minute session. At the end of each open field test session theOF chambers are thoroughly cleaned.

Typically ten to twelve mice are tested in each group. Test compounddoses typically range from 0.01 mg/kg to 50 mg/kg.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons where appropriate. An effect is considered significant ifp<0.05. Data are represented as the mean and standard error to the mean(s.e.m).

Example 15B Determination of the Effect of Compounds of the Invention onGlutamate-Induced ⁴⁵Ca^(2±) Uptake into Synaptosomes of Cortex of RatBrain

Methods

Synaptosomes were obtained from cerebral cortex of newborn (9-10 days)Wistar rats using standard Hajos method. The brain was homogenized with10 volumes of cooled 0.32 M sucrose at 900 rpm. The homogenate wascentrifuged at 1500 g for 10 min. and the resulted supernatant wascentrifuged at 10000 g for 20 min. The radioactive label was accumulatedby suspension of the synaptosomal P₂-fraction in the incubation buffer Ahaving the following composition: 132 mM NaCl, 5 mM KCl, 5 mM HEPES, 10mM glucose, pH 7.4 (protein concentration of approximately 1.5-2 mg/ml).The mixture was further incubated for 5 min with 200 μM glutamate at 37°C. and then ⁴⁵Ca²⁺ uptake was stopped by filtration through GF/B filters(Whatman, England) followed by three washes with cold buffer B (145 mMKCl, 10 mM Tris, 5.4 mM Trilon B, pH 7.4). The radioactivity probes wereanalyzed by fluid scintillation beta-analyzer (TriCarb, Perkin Elmer).All tests were performed in three parallel trials in 2-3 independentexperiments. The amount of ⁴⁵Ca²⁺ uptake was estimated by calculatingthe difference of radioactive label during the stimulation withglutamate and without the stimulation with agonist. The result ispresented as percents with respect to the control measurement which was100%.

Specific ⁴⁵Ca²⁺ uptake was estimated using the following equation:K _((43/21))=[(Ca₄−Ca₃)/(Ca₂−Ca₁)]100%,where

Ca₁—⁴⁵Ca²⁺ uptake for the Control (without glutamate and the compoundtested),

Ca₂—glutamate-induced ⁴⁵Ca²⁺ uptake (glutamate only),

Ca₃—⁴⁵Ca²⁺ uptake in the presence of the compound tested (withoutglutamate),

Ca₄—⁴⁵Ca²⁺ uptake in the presence of glutamate and the testing compound.

Statistical analysis of the results was performed using Student'st-test.

Results

The effect of dimebon on a glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. Dimebon inhibited ⁴⁵Ca²⁺uptake into synaptosomes at a concentration of 0.25-10 μM. The maximalinhibition ⁴⁵Ca²⁺ uptake into synaptosomes was observed at aconcentration of 1 μM dimebon (40%). At concentrations of 0.1 μM and 100μM, dimebon caused an increase of glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex (120.4% and 132%, accordingly) (Table 10,FIG. 5A).

The effect of compound C 4-1 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. Compound C 4-1 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of rat cortex at aconcentrations of 0.1-0.5 μM by about 20%. With increasingconcentrations of C 4-1 glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes increased. The maximal increase of glutamate-induced ⁴⁵Ca²⁺uptake into synaptosomes was observed at a concentration of 5 μM C 4-1(128% of the control) (Table 10, FIG. 5A).

The effect of compound C 4-4 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. Compound C 4-4 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of rat cortex at aconcentration of 0.5 μM. The maximal inhibition ⁴⁵Ca²⁺ uptake wasobserved at a concentration of 1 μM (20.5%). Increasing concentrations(50-100 μM) of C 4-4 caused an increase in glutamate-induced ⁴⁵Ca²⁺uptake into synaptosomes of rat cortex. The maximal increase ofglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes was observed at aconcentration of 50 μM C 4-1 (137.5% of the control) (Table 10, FIG.5A).

The effect of compound C 4-5 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. Compound C 4-5 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes at a concentrations of1-25 μM. The maximal inhibition (40%) was observed at a concentration of10 μM C 4-5. At concentrations of 0.5-0.1 μM and at concentrations of50-100 μM, compound C 4-5 caused an increase in glutamate-induced ⁴⁵Ca²⁺uptake into synaptosomes of rat cortex. The maximal increase inglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes was observed atconcentrations of 100 μM and 0.1 μM C 4-5 (148.4% and 136.4%,accordingly) (Table 10, FIG. 5A).

TABLE 10 Effect of dimebon, C 4-1, C 4-4 and C 4-5 on glutamate- induced⁴⁵Ca²⁺ uptake into synaptosomes of rat cortex. % Ca of control(control - 100%) C, μM Dimebon C 4-1 C 4-4 C 4-5 0.1  120 ± 3.3  79.4 ±6.1 111.2 ± 9.2  136.4 ± 11.8 0.25 77.2 ± 6.0 — — — 0.5  64.4 ± 12.4 79.2 ± 10 81.8 ± 14  124.6 ± 13.7 1.0 61.3 ± 8.1 106.1 ± 7.9 79.5 ±11.1 99.8 ± 0.1 5.0 83.2 ± 4.1  128 ± 4.5 97.9 ± 4.3  84.2 ± 0.7 10 89.3± 1.2 107.6 ± 3.5 99.9 ± 11.7 59.9 ± 0.2 25 97.2 ± 8.5 114.3 ± 0.5 93.6± 15.7 98.6 ± 9.4 50 98.7 ± 8.8 110.1 ± 5.1 137.5 ± 5.4  111.7 ± 11.2100  132 ± 2.9 115.9 ± 8.8 125.3 ± 11.2  148.4 ± 7.3 

The effect of compound C 4-6 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. C 4-6 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes at a concentration of5-10 μM. With increasing concentrations (50-100 μM) compound C 4-6caused an increase in glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomesof rat cortex. The maximal increase in glutamate-induced ⁴⁵Ca²⁺ uptakeinto synaptosomes was observed at a concentration of 100 μM (152.2% ofthe control) (Table 11, FIG. 5B).

TABLE 11 Effect of C 4-6, C 4-7, C 1-1, C 1-5, C 1-7 on glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of rat cortex. % Ca of control(control - 100%) C, μM C 4-6 C 4-7 C 1-1 C 1-5 C 1-7 0.1 103.6 ± 11.4 97.2 ± 5.5 85.5 ± 5.8  96.3 ± 5.6  77.5 ± 2.4 0.5  96.9 ± 11.9  87.6 ±3.9 86.9 ± 4.2  77.5 ± 0.8  72.7 ± 0.3 1.0 105.5 ± 5.2  105.3 ± 2.8100.3 ± 6.5    94 ± 3.4  98.6 ± 2.4 5.0 86.5 ± 6.1 109.2 ± 10  98.8 ±3.2   96 ± 1.5 131.8 ± 8.8 10 88.6 ± 2.8 101.6 ± 7.8   91 ± 11.9 117.2 ±1.3 134.5 ± 9.2 50 122.1 ± 8.5  128.3 ± 8.1 126.9 ± 4.5  115.4 ± 4.8126.7 ± 7.7 100 152.0 ± 6.7  123.6 ± 4.9 111.9 ± 11.3 130.1 ± 7.4 139.8± 6.5

The effect of compound C 4-7 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. C 4-7 did not affectglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes at a concentration of0.1-10 μM. At a concentration of 50-100 μM, compound C 4-7 caused anincrease in glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of ratcortex (˜128% of the control) (Table 11, FIG. 5B).

The effect of compound C 1-1 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. C 1-1 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes (˜13%) at aconcentration of 0.1-0.5 μM. With increasing concentrations (50-100 μM)compound C 1-1 caused an increase in glutamate-induced ⁴⁵Ca²⁺ uptakeinto synaptosomes. The maximal increase in glutamate-induced ⁴⁵Ca²⁺uptake into synaptosomes was observed at a concentration of 50 μM(126.9% of the control) (Table 11, FIG. 6A).

The effect of compound C 1-5 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. Compound C 1-5 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes: at a concentrationsof 0.5 μM by about 22.5%. Compound C 1-5 caused an increase inglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of rat cortex at aconcentration of 100 μM (130% of the control) (Table 11, FIG. 6A).

The effect of compound C 1-7 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. Compound C 1-7 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes: at a concentration of0.1-0.5 μM inhibition was ˜27.3%. Compound C 1-7 caused an increase inglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of rat cortex at aconcentration of 5-100 μM. The maximal increase in glutamate-induced⁴⁵Ca²⁺ uptake into synaptosomes was observed at a concentration of 100μM (139.8% of the control) (Table 11, FIG. 6B).

The effect of compound C 1-6 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. C 1-6 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes (inhibition ˜20%) at aconcentration of 5 μM. At a concentration of 0.1-1 μM and 10-100 μMcompound C 1-6 caused an increase in glutamate-induced ⁴⁵Ca²⁺ uptakeinto synaptosomes of rat cortex. The maximal increase inglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes was observed at aconcentration of 0.5 μM and 100 μM (142% and 140.8% of the control,accordingly) (Table 12, FIG. 6C).

The effect of compound C 1-8 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. C 1-8 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes (inhibition ˜14%) at aconcentration of 1-5 μM. At concentrations 50-100 μM, compound C 1-8caused an increase in glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomesof rat cortex (˜122% of control) (Table 12, FIG. 6D).

The effect of compound C 1-4 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. Compound C 1-4 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes (inhibition ˜12.6%) ata concentration of 0.5 μM. At concentrations 50-100 μM, compound C 1-4caused an increase in glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomesof rat cortex (˜131% of control) (Table 12, FIG. 6D).

The effect of compound C 4-3 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. C 4-3 in did not affectglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes at a concentration of0.1-50 μM. At concentrations 50-100 μM compound, C 4-3 caused anincrease in glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of ratcortex (˜126% of control) (Table 12, FIG. 7).

The effect of compound C 2-1 on glutamate-induced ⁴⁵Ca²⁺ uptake intosynaptosomes of rat cortex was investigated. C 2-1 did not affectglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes at a concentration of0.1-1 μM. At concentrations 5-50 μM, compound C 2-1 inhibitedglutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes. The maximalinhibition of glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes was 30%at a concentration of 10 μM (Table 12, FIG. 7).

TABLE 12 Effect of compounds C 1-6, C 1-8, C 1-4, C 2-1 on glutamate-induced ⁴⁵Ca²⁺ uptake into synaptosomes of rat cortex. % Ca of control(control - 100%) C, μM C 1-6 C 1-8 C 1-4 C 4-3 C 2-1 0.1 130.1 ± 8.699.2 ± 1.4 99.1 ± 2.5 93.2 ± 3.0 90.5 ± 5.1 0.5  142 ± 6.4 96.7 ± 2.487.4 ± 3.7 92.1 ± 3.3 94.8 ± 3.0 1 121.8 ± 4.4 86.1 ± 0.1 96.2 ± 5.0101.0 ± 1.0   94.5 ± 11.8 5  79.3 ± 11.8 87.7 ± 2.7 94.9 ± 5.7 93.7 ±6.8  80 ± 3.0 10 100.2 ± 6.7 99.3 ± 3.0 94.3 ± 2.7 94.7 ± 6.9 69.9 ± 4.450 127.7 ± 0.7 122.4 ± 1.6  112.7 ± 10.1 117.9 ± 6.0   90 ± 6.1 100  140± 7.4 121.7 ± 13.9 131.5 ± 0.1  125.6 ± 3.9  104.2 ± 12.8

Example 16B Determination of the Effect of Compounds of the Invention onAMPA-Receptor Activity

Methods

The analysis of effects of the testing compounds on AMPA receptors wascarried out using an electrophysiological patch-clamp method in wholecell configuration (Hamill et al., 1980) of the Purkinje cell freshisolated from the cerebellum of juvenile rats (12-15 days). Theisolation was carried out using a modified method (Kaneda et al., 1988)in which cerebral 400-600 μm sections were incubated for 60 min in thetemperature controlled chamber in 10 mL of buffer solution (150 mM NaCl,5 mM KCl, 2 mM CaCl₂, 2 mM MgSO₄.7H₂O, 10 mM HEPES, 15 mM glucose, pH7.42). The incubation solution was exchanged with the incubation bufferwith pronase (2 mg/mL) and collagenase (1 mg/mL) for 70 min. After a 20min wash with the original buffer, all sections were placed into thePetri dish and were separated using a Pasteur pipette. All solutionswere constantly aerated with 100% O₂ at 34° C. The composition ofextracellular saline was: 150 mM NaCl, 5 mM KCl, 2.6 mM CaCl₂, 2 mMMgSO₄.7H₂O, 10 mM HEPES, 15 mM glucose, pH 7.36. The transmembranecurrent was induced as a result of the activation of AMPA receptors by asuperfusion with the agonist solution (kainic acid). The currents weremeasured using borosilicate microelectrodes (resistance 2.5-4.0 mOhms)filled with 100 mM KCl, 11 mM EGTA, 1 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES,5 mM ATP, pH 7.2. The currents were registered using EPC-9 (HEKA,Germany) and recorded with Pulse software package which was alsopurchased from HEKA. The analysis of observations was carried out usingPulsefit (HEKA, Germany) and the statistical significance was analyzedusing a Student's T-test criteria. Data are presented as mean±SEM in %of control values.

Results

Compounds of the invention were tested in 3-5 neurons. Everyconcentration of compound was repeated three-four times in every neuron.Data are presented as mean±SEM in % of Control values (Table 13+14,FIGS. 8-12). Control value=100%.

TABLE 13 The action of the new derivatives on the kainic acid-inducedcurrents in Purkinje cells. Compounds 10⁻⁹ M 10⁻⁸ M 10⁻⁷ M 10⁻⁶ M 10⁻⁵ M3 × 10⁻⁵ M C4-1 125 ± 6 147 ± 11 115 ± 3  110 ± 5  97 ± 4 not testedC4-5 100 131 ± 3  133 ± 5  108 ± 7  106 ± 6  not tested C4-4 100 129 ±5  147 ± 15 142 ± 11 150 ± 26 150 ± 20 C4-6 not tested 100 ± 3  120 ± 20140 ± 25 152 ± 30 149 ± 33 C4-7 not tested 95 ± 8 118 ± 12 109 ± 17 106± 14 101 ± 9  C1-1 100 ± 3 149 ± 25 148 ± 14 98 ± 2 105 ± 8  95 ± 6 C1-5 64 ± 8  62 ± 12  70 ± 23  64 ± 23 126 ± 18 not tested

TABLE 14 The action of the new derivative series C on the kainicacid-induced currents in Purkinjecells. Compounds 10⁻⁹ M 10⁻⁸ M 10⁻⁷ M10⁻⁶ M 10⁻⁵ M 3 × 10⁻⁵ M C1-6 100 ± 3 101 ± 4 116 ± 7 146 ± 12 135 ± 1130 ± 6  C1-4 129 ± 9 119 ± 6 114 ± 5 109 ± 12 100 ± 9 not tested C1-8not tested 100 ± 4 102 ± 3 123 ± 8  105 ± 8 90 ± 7 C4-3 100 ± 3  145 ±12  149 ± 15 139 ± 11 100 ± 6  80 ± 10

Example 17B Influence of Compounds on Mitochondria

Methods

Rat liver and brain mitochondria were prepared from male Wistar rats.The rats were euthanized in a CO₂ chamber followed by decapitation theprocedure being in compliance with the Guidelines for Animal Experimentsat IPAC RAS.

Mitochondria from rat liver were isolated via the standard mannitoldifferential centrifugation protocol in sufficient buffer A, whichcontained 210 mM mannitol, 70 mM sucrose, 5 mM HEPES, 0.25 mM EDTA pH7.4, at 4° C. and resuspended in buffer A without EDTA for the study ofmPT.

Brain mitochondria were isolated from the pooled forebrains of two rats.The modified method of Sims was used to isolate and purify brainmitochondria in a Percoll gradient. The brain was homogenized in “bufferA” (225 mM mannitol, 75 mM sucrose, 5 mM HEPES, 1 mM EGTA, pH 7.4 [KOH])and centrifuged for 10 min at 1300 g. The supernatant was centrifugedfor 10 min at 10000 g, and then the pellet was suspended in 15% Percolland layered on a discontinuous gradient consisting of 40 and 23%Percoll, respectively, which was then centrifuged for 10 min at 30000 gwithout using brakes. The mitochondria were collected from the interfaceof the lower two layers and after resuspension in “buffer A”, thesuspension was centrifuged at 16600 g for 10 min, then the pellet wasresuspended in “buffer A”, BSA (10 mg/mL) was added to bind free fattyacids; and the suspendions was centrifuged again at 6300 g for 10 min.Following centrifugation the pelleted mitochondria were re-suspended inisolation medium without EGTA to achieve a protein concentration of15-20 mg/ml.

Swelling Assay.

Mitochondrial swelling caused by influx of solutes through open PT poresresults in an increase in light transmission (i.e., a reducedturbidity). This turbidity change offers a convenient and frequentlyused assay of the MPT by measurement of absorbance in mitochondrialsuspensions. In the present study, the MPT induced by Ca²⁺ and inorganicphosphate (Ca/Pi) was monitored by absorbance changes at 540 nm in acuvette in a Beckman DU 640 spectrophotometer in 1 ml of buffer A plus0.8 μM rotenone, 5 mM succinate, 1 mM KH₂PO₄ and 0.5 mg or 0.2 mgprotein of isolated liver or brain mitochondria, accordingly. Reactionwas started by the addition of triggering agent (Ca²⁺). Pre-treatmentand reaction were performed at 30° C. Swelling rate was quantified asΔA₅₄₀/min/mg, calculated, in all cases, from a tangent to the steepestportion of the plot of A₅₄₀ versus time.

Measurement of Mitochondrial Membrane Potential.

The same experimental conditions were used for the assessment ofalterations of the mitochondrial membrane potential, except thatsafranine was included in incubation medium at a final concentration of10 mkM and succinate was added before the compounds of the invention.This concentration of safranine was determined before hand as theoptimal compromise between signal/baseline ratio and interference ofsafranine itself with swelling induced by Ca/Pi (safranine tended toenhance Ca/Pi-induced swelling at concentrations above 20 mkM). Changesin the status of the mPT pore were assessed spectrophotometrically at554 and 524 nm in a cuvette in a Beckman DU 640 spectrophotometer.A₅₅₄₋₅₂₄ represents the characteristics of mitochondrial potential andA₅₅₄-characteristics of mitochondrial swelling.

Measurement of Calcium Retention Capacity of Mitochondria.

Analyses of extramitochondrial Ca²⁺ following a bolus dose of Ca²⁺ wereperformed under energized conditions, in a sucrose based buffer (250 mMsucrose, 10 mM HEPES, 1 mM Pi (K), 1 mM MgCl₂, 10 μM EGTA, pH 7.2)containing 5 mkM Arsenazo III, 1 μg/ml oligomycin and 20 μM ADP with 5mM malate and glutamate as respiratory substrates in a cuvette in aBeckman DU 640 spectrophotometer.

Results

Ca²⁺-induced Swelling of mitochondria was used as the primary screeningtest for compounds influence on MPT pore opening. IC₅₀ was estimated asthe concentration of compound which reduces up to 50% the initial rateof turbidity fall after calcium addition. But the inhibition of swellingmay be connected not only with direct inhibition of MPT pore opening butalso with the impairment of respiratory function of mitochondria andwith the compounds action on calcium transport into mitochondria. Forthe primary estimation of these possibilities the mitochondrial membranepotential and calcium retention capacity of mitochondria were measured.According to the experimental data (Table 15) it is suggested that atleast particularly the inhibition of MPT by C 4-1, C 4-4, C 4-6 and C1-5 was accompanied with impairment of mitochondrial respiratoryfunctions. New synthesized compounds (except C-14 and C-43) aloneinduced an increase of brain mitochondria suspension turbidity. Themechanism of such effect needs additional investigations.

TABLE 15 Influence of compounds on functional characteristics of ratbrain mitochondria. A₅₄₀ increase IC₅₀ μM, Ca²⁺- in mitochondrialinduced (25-50 μM) suspension after Depolar- Com- swelling of brainaddition of 100 μM of ization of pound mitochondria compound (rel.units) mitochondria Dimebon 66 ± 26 1 − C1-1 15 ± 16 16 − C1-4 93.9 ±16.4 1 − C1-5 18 ± 16 30 + C1-6 12.7 ± 6.2  1.5 C-16 react withsafranine C1-7 28 ± 6  >30 − C1-8 6.25 ± 6.25 25 C-18 react withsafranine C4-1 3.9 ± 1.6 10 + C4-3 76.0 ± 12.0 1 − C4-4 6.7 ± 1.2 14 +C4-5 28 ± 6  3 − C4-6 6.0 ± 1.2 28 + C4-7 9.9 ± 3.4 8 −

Compounds C-1-6 and C-1-8 decreased the calcium-induced swelling ofbrain mitochondria with IC₅₀ near 12 μM and 6 μM, respectively, but athigher concentrations a decrease of the effect (FIG. 13) and significantelevation of mitochondrial suspension absorbance after addition of 100μM C-18 was observed (Table 15). Both compounds increased thecalcium-retention capacity of mitochondria at concentrations near theIC₅₀.

In a safranine test, C-1-6 and C-1-8 revealed depolarizing activity, butboth compounds did react with safranine in buffer without mitochondria.

Compounds C-1-4 and C-4-3 decreased the calcium-induced swelling ofbrain mitochondria with an IC₅₀ near 94 μM and 76 μM, respectively(Table 15, FIG. 13). No depolarization of brain mitochondria by thesecompounds was observed at concentrations up to 100 mkM.

Example 18B Influence of Compounds on Spatial Memory Performance andPerformance on the Recognition Memory Task (Object Recognition Test)

The object recognition test is based on the fact that mice and ratsspontaneously explore new object or location of a known object a lotlonger than the know object or a known location of an object. This testwas first used in rats (Ennaceur A., Delacour J., 1988). It was furthershown by others that this type of memory testing is suitable for mice(Dodart J. et al. 1997, Messier C. 1997, Pittenger C. et al., 2002,Ryabinin A. et al., 2002, Sargolini F. et al., 2003). The method ofrecognition of an object is divided in two stages. The first oneinvolves the recognition of a new location of a known object, which isused to assess spatial memory. The second one includes a test forrecognition of a new in order to evaluate the non-spatial memory (GaffanD., 1992, Kolb B. et al., 1994, Steckler T., 1998). Currently, both arewidely used to determine the effectiveness of newly synthesized drugs onmemory.

Materials and Methods

All experiments were carried out on 3-4 months old males (C57BL/6 line)22-26 g weight with 10 animals in each group. All animals were kept inthe animal facility (5 animals per cage) on the 12×12 hours light cycle(8 am-8 pm) with free access to food and water. The observation chamberwas made of non-transparent white plastic 48×38×30 cm (18.9×14.9×11.8inches). Brown glass vials were used as test objects which are 2.7 cm indiameter (1.1 inch) and 5.5 cm high (2.2 inch). All vials were treatedwith 85% ethanol 2-3 minutes before each testing. Animals were placed inthe center of the chamber.

Dimebon and compounds of the invention were dissolved in distilled waterand administered orally at 0.05 mL per 10 g of animal mass 1 hour beforethe training exercise. All animals in the control group were treatedwith the equivalent dose of vehicle. The testing was performed 48 hoursafter the training exercise because animals forget the location of theobject during the 48-hour resting time.

Experimental Procedures

Recognition of a New Location of the Known Object (Spatial MemoryPerformance)

Habituation with the Testing Chamber

On the first day animals were brought in the testing room so that theycould adapt to the testing environment for 20-30 min. Subsequently, eachanimal was placed in the empty testing chamber for 10 min, which waswiped with alcohol beforehand. After that animals were transferred backinto the chamber and returned to the animal facility.

Training Exercise

The next day after habituation, the animals were brought back into thetesting room where they were weighed and injected with the testingcompound. An hour after injection, each animal was placed into thetesting camber which had two identical objects that were positioned 14.5cm (5.7 inches) from the corners on the diagonal. The training exerciselasted for 15 min for each animal. Subsequently, each animal was placedback into the cage and returned into the animal house.

Testing Procedure

The testing procedure was performed 48 hours after the trainingexercise. During the procedure two objects were used as in the trainingexercise. One object was left in the old position whereas another wasplaced in a new location. The amount of time that each animal spent onexploration each object was determined with 0.1 sec accuracy using twoelectronic stopwatches for total of 10 min. Animals were observedthrough minors. The survey of the object was counted as positive if thenose of an animal was pointed within 2 cm or if the animal was touchingthe objected directly with the nose.

Recognition of the New Object (Non-Spatial Performance on theRecognition Memory Task)

The following experiment was also performed on 3-4 months old males(C57BL/6 line) with 10 animals in each group. All animals were kept inthe animal facility (5 animals per cage) on the 12×12 hours light cycle(8 am-8 pm) with free access to food and water. However, in this case around bottom testing chamber 52 cm in diameter (20.5 inches) and 34 cm(13.4 inches) high was used. Similarly, brown glass vials were used astest objects which are 2.7 cm in diameter (1.1 inch) and 5.5 cm high(2.2 inch). The testing compounds were administered orally at 0.05 mLper 10 g of animal mass 1 hour before the training exercise. All animalsin the control group were treated with the equivalent dose of vehicle.The testing was performed 48 hours after the training exercise becauseanimals forget the location of the object during the 48-hour restingtime.

The experimental procedure was identical to the previously describedtest (Recognition of a new location of a known object). The majordifference is in the testing procedure which involved one known object(brown glass vial) and one unknown object. The second glass vial wassubstituted with metallic cylinder 3 cm (1.2 inches) in diameter and 4.5cm (1.8 inches) high.

Statistical Data Analysis

Due to fair differences in the amount of time that each animal surveyedthe object, the percentage of the survey time for each animal wasdetermined using this formula: tNL/(tFL+tNL)×100 (where t is time,NL—new location (object), and FL—familiar location (object)). As 100%was taken the total amount of time that animals explored both objects.Subsequently, the statistical significance was analyzed using aStudent's t-test criteria.

Results

Comparative Assessment of Dimebon Effect on Spatial and Non-SpatialMemory in Object Recognition Test

1. Effects of Dimebon on Memory in the New Object Recognition Test

In this experiment dimebon was administered in a wide dose range (from0.005 mg/kg to 2.0 mg/kg) 1 hour prior to training. As a result, it wasfound that at 0.005 mg/kg dimebon had a memory activating effect. Themaximum effect was registered at 0.05 mg/kg. In this group animals spent65.6±4.4% to recognize the new object, whereas 34.4±4.4% of the totaltime was spent to recognize the known object (P=0.0003). Furtherincrease of the exposure dose resulted in the decrease of thestimulating effect. In addition, the results of the experiment at 0.5mg/kg were not statistically significant. However, further increase ofthe exposure dose up to 1-2 mg/kg, the stimulating effect on memoryreturned (FIG. 14). Therefore, it was shown that dimebon has a two-phaseactivating effect on the non-spatial memory, which may be linked to atleast two different mechanisms of its activating effect.

2. Effects of Dimebon on Memory in the Recognition Test of a KnownObject in a New Location

It was previously shown that dimebon at 0.01-0.1 mg/kg has adose-dependent activating effect on memory in the test for recognitionof a known object in a new location. However, this effect disappears at0.25 mg/kg, and thus it was important to test whether the second phaseof the activating wave would appear at higher doses of dimebonexposures. As a result, it was shown that only at 10 mg/kg dimebon had apronounced stimulating effect on memory. Animals in this group spent61.2±5% of the total time to explore the known object in a new location,and 38.8±5% in a known position (P=0.0003) (FIG. 15). Hence, it wasconcluded that dimebon also has a two-phase stimulating effect on thespatial memory (as shown in the recognition test of a known object in anew location); however much higher doses of this drug are required.

Effects of Compounds on Memory in the Recognition Test of a Known Objectin a New Location

A test was conducted to assess recognition of a new location of afamiliar object to study the effects on memory of C 4-1, C 4-4, C 4-5, C4-6, C 4-7, C 1-1 and C 1-5.

Control animals 48 hours after the training exercise explored objectsapproximately the same time in the known and new location. Thus, theyforgot the location of the object during training. However, the C 4-1treated animals (0.1 mg/kg) explored the object 61.3±6.9% of the totaltime in a new location and 38.7±6.9% in the known position (P=0.0004).Results in other groups (0.05 mg/kg, 0.5 mg/kg, and 1 mg/kg) were notsignificantly different from the control group (FIG. 16). Therefore, C4-1 had an activating effect on memory only at 0.1 mg/kg.

Studies with C 4-4 showed that at 0.05 mg/kg it had no effect on timethat animals explore the object in a known or new location. However, thegroup of animals that was treated with 0.1 mg/kg of C 4-4 explored theobject 58.5±9.6% of the total time in a new location and 41.5±9.6% inthe known position (P=0.01). Mice that were treated with 0.5 mg/kg of C4-4 explored the object 59.1±4.2% of the total time in a new locationand 40.9±4.2% in the known position (P=0.0003). Similar results wereobtained in mice that were treated with 1 mg/kg of C 4-4 (FIG. 17). C4-4 had an activating effect on memory which is preserved for about 48hours after training. This effect was similar to C 4-1, but C 4-4 had awider range of effective doses.

The C 4-5 was tested at 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg and 1 mg/kg inthe recognition test of new location of a known object. The 0.5 mg/kggroup explored the object in a new location for 56.2±7.6% of the totaltime and 43.8±7.6% in the known position (P=0.03). As dose was increasedto 1 mg/kg animals explored the object in a new location for 60.6±8.4%of the total time and 39.4±8.4% in the known position (P=0.006). The0.05 mg/kg and 0.1 mg/kg doses were not effective (FIG. 18). Therefore,C 4-5 stimulated memory, but its activity was approximately 10 timesweaker than the one of C 4-1 and dimebon.

Animals treated with compound C 4-6 at a concentration of 0.5 mg/kgexplored the object in a new location for 61.0±4.8% of the total timeand 39.0±4.8% in the known position (P=0.0007). As the dose wasincreased to 1 mg/kg, animals explored the object in a new location for56.3±7.7% of the total time and 43.7±7.7% in the known position(P=0.03). The 0.05 mg/kg and 0.1 mg/kg doses were not effective (FIG.19). Therefore, C 4-6 stimulated memory, but its activity wasapproximately 5 times weaker than the one of dimebon.

The compound C 4-7 was tested at 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg and 1mg/kg in the recognition test of new location of a known object. It wasdetermined that the 0.1 mg/kg group explored the object in a newlocation for 63.4±10.4% of the total time and 36.6±10.4% in the knownposition (P=0.01). The 0.05, 0.5 and 1 mg/kg doses were not effective(FIG. 20). Therefore, C 4-7 stimulated memory and has similar activityas dimebon, but it had a much more narrow range of the effective doses.

A rather interesting memory activating effect of C 1-1 was discovered incase testing of a two phase effect of dimebon on spatial memory. Micethat were injected with 0.05 mg/kg of C 1-1 spent 61.8±8.4% of the totaltime and 38.2±8.4% in the known position (P=0.002). When the dose wasincreased up to 0.1 mg/kg, animals spent 56.0±6.9% of total time tolocate the object in the new location and 42.7±6.9% in the knownposition (P=0.02). In addition, further increase to 0.5 mg/kg resultedin the disappearance of the stimulating effect on memory. However, agroup of mice that was injected with C-1-1 at 1 mg/kg explored theobject in the new location for 61.5±8.9% of total time and 37.8±8.9% inthe known position (P=0.002). In other words, once again a stimulatingeffect was observed (FIG. 21). C 1-1 had a stimulating effect on memory.The activity of this compound was approximately two times higher thanthe one of dimebon, but in comparison C 1-1 had a two-phase responseeffect. Though, the second stimulating phase appeared at concentrationsof C 1-1 10 times less than it was shown for dimebon. It is quite likelythat the stimulating effect of this compound on spatial memory will bemuch higher than the one shown for dimebon.

Studies with C 1-5 showed that at 0.05 mg/kg it had no effect on theamount of time animals explore the object in a known or new location.However, the group of animals that was treated with 0.1 mg/kg of C 1-5explored the object 57.9±7.5% of the total time in a new location and42.1±7.5% in the familiar position (P=0.01). Treatment with 0.5 mg/kg ofC 1-5 resulted in the disappearance of the stimulating effect on memory.However, at increasing dosages up to 1 mg/kg animals explored object innew localization 57.4±8.4% of time and in familiar—42.6±8.4% (P=0.03).On the basis of the received results the conclusion that C 1-5 had astimulating effect on memory and on activity was at a level dimebon.Also as C 1-1 this compound had a two-phase stimulating effect (FIG.22).

The results are summarized in Table 16.

TABLE 16 Influence of various doses of connections of series C on memoryin the test recognition new localization of known object Dose ofCompound in mg/kg Compound 0.05 0.1 0.5 1.0 C 4-1 − + − − C 4-4 − + + +C 4-5 − − + + C 4-6 − − + + C 4-7 − + − − C 1-1 + + − + C 1-5 − + − +Dimebon + + − − + the dose has an activating effect on memory − noactivating effect on memory was discovered for the dose

REFERENCES

-   Dodart J. C., C. Mathis and A. Ungerer, Scopolamine-induced deficits    in a two-trial object recognition task in mice. NeuroReport 8    (1997), pp. 1173-1178.-   Ennaceur A. and J. Delacour, A new one-trial test for    neurobiological studies of memory in rats. 1: behavioral data.    Behav. Brain Res. 31 (1988), pp. 47-59.-   Kolb B., K. Buhrmann, R. McDonald and R. Sutherland, Dissociation of    the medial prefrontal, posterior parietal, and posterior temporal    cortex for spatial navigation and recognition memory in the rat.    Cereb. Cortex 6 (1994), pp. 664-680.-   Messier C., Object recognition in mice: improvement of memory by    glucose. Neurobiol. Learn. Mem. 67 (1997), pp. 172-175.-   A. E. Ryabinin, M. N. Miller and S. Durrant, Effects of acute    alcohol administration on object recognition learning in C57BL/6J    mice. Pharmacol. Biochem. Behav. 71 (2002), pp. 307-312.-   Sargolini F., P. Roullet, A. Oliverio and A. Mele, Effects of    intra-accumbens focal administrations of glutamate antagonists on    object recognition memory in mice. Behav. Brain Res. 138 (2003), pp.    153-163.-   Sik A., van Nieuwehuyzen, J. Prickaerts, A. Blokland, Performance of    different mouse strains in an object recognition task. Behav. Brain    Res. 147 (2003), pp. 49-54.-   Steckler T., W. H. I. M. Drinkenburgh, A. Sahgal and J. P. Aggleton,    Recognition memory in rats. I. Concepts and classification. Prog.    Neurobiol. 54 (1998), pp. 289-311.-   Steckler T., W. H. I. M. Drinkenburgh, A. Sahgal and J. P. Aggleton,    Recognition memory in rats II. Neuroanatomical substrates. Prog.    Neurobiol. 54 (1998), pp. 313-332.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A compound of the Formula (E):

or a salt thereof, wherein: R¹ is H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substitutedor unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl orcarbonylalkylenealkoxy; wherein acyl is selected from the groupconsisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—,alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substitutedalkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—; wherein sulfonylamino is selected from the groupconsisting of —SO₂NH₂, —SO₂NR-alkyl, —SO₂NR-substituted alkyl,—SO₂NR-alkenyl, —SO₂NR-substituted alkenyl, —SO₂NR-alkynyl,—SO₂NR-substituted alkynyl, —SO₂NR-aryl, —SO₂NR-substituted aryl,—SO₂NR-heteroaryl, —SO₂NR-substituted heteroaryl, —SO₂NR-heterocyclic,and —SO₂NR-substituted heterocyclic, where R is H or alkyl, or —SO₂NR₂,wherein the two R groups are taken together and with the nitrogen atomto which they are attached to form a heterocyclic or substitutedheterocyclic ring; wherein sulfonyl is selected from the groupconsisting of —SO₂-alkyl, —SO₂—substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substituted alkynyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, and —SO₂-substituted heterocyclic; eachR^(2a) and R^(2b) is independently H, substituted or unsubstituted C₁-C₈alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acarbonyl moiety or R^(2a) and R^(2b) are taken together with the carbonto which they are attached to form a cycloalkyl moiety; each R^(3a) andR^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, hydroxyl, alkoxy, cyano, nitro or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or R^(3a) and R^(3b) are taken together with the carbon to whichthey are attached to form a cycloalkyl moiety; each X⁷, X⁸, X⁹ and X¹⁰is independently CR⁴; m and q are independently 0 or 1, provided that atleast one of m and q is 1; each R⁴ is independently H, hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, carboxy, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; whereinacyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—,substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—,alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substitutedaryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—,heterocyclic-C(O)—, and substituted heterocyclic-C(O)—; whereinsulfonylamino is selected from the group consisting of —SO₂NH₂,—SO₂NR-alkyl, —SO₂NR-substituted alkyl, —SO₂NR-alkenyl,—SO₂NR-substituted alkenyl, —SO₂NR-alkynyl, —SO₂NR-substituted alkynyl,—SO₂NR-aryl, —SO₂NR-substituted aryl, —SO₂NR-heteroaryl,—SO₂NR-substituted heteroaryl, —SO₂NR-heterocyclic, and—SO₂NR-substituted heterocyclic, where R is H or alkyl, or —SO₂NR₂,wherein the two R groups are taken together and with the nitrogen atomto which they are attached to form a heterocyclic or substitutedheterocyclic ring; wherein sulfonyl is selected from the groupconsisting of —SO₂-alkyl, —SO₂—substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substituted alkynyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, and —SO₂-substituted heterocyclic; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,C₁-C₈ alkyl, carboxy, carbonylalkoxy, or is taken together with thecarbon to which it is attached and a geminal R⁸ to form a cycloalkylmoiety, provided that at least one of R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) is other than H; each R^(10a) and R^(10b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo,hydroxyl, alkoxy, cyano, nitro or R^(10a) and R^(10b) are taken togetherwith the carbon to which they are attached to form a carbonyl moiety orR^(10a) and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety; and Q is a substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylor substituted or a unsubstituted heterocyclyl.
 2. The compound of claim1, or a salt thereof, wherein at least one of R^(8c), R^(8d), R^(8e),and R^(8f) is other than H.
 3. The compound of claim 1, or a saltthereof, wherein at least one of R^(8e) and R^(8f) is other than H. 4.The compound of claim 3, or a salt thereof, wherein X⁷, X⁸ and X¹⁰ areeach CR⁴ where R⁴ is H, and X⁹ is CR⁴ where R⁴ is substituted orunsubstituted C₁-C₈ alkyl, perhaloalkyl, or halo.
 5. The compound ofclaim 4, or a salt thereof, wherein X⁹ is CR⁴ where R⁴ is methyl, CHF₂,CH₂F, CF₃, chloro or fluoro.
 6. The compound of claim 1, or a saltthereof, wherein at least one of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) is C₁-C₈ alkyl.
 7. The compound of claim 6, or a saltthereof, wherein the compound has one or more of the followingstructural features: R¹ is methyl; Q is a substituted or unsubstitutedpyridyl; and X⁹ is CR⁴ where R⁴ is halo, a substituted or unsubstitutedC₁-C₈ alkyl, or perhaloalkyl.
 8. The compound of claim 1, or a saltthereof, wherein at least one of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) is methyl.
 9. The compound of claim 1, or a salt thereof,wherein —R^(8c)R^(8d)—R^(8e)R^(8f)— and the carbons to which they areattached are taken together to form a moiety selected from the groupconsisting of —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—CH₂—, —CH₂—C(CH₃)(CH₃)—,—C(CH₂CH₂)—CH₂— and —CH₂—C(CH₂CH₂)—.
 10. The compound of claim 1, or asalt thereof, wherein q is 0, and m is
 1. 11. The compound of claim 1,or a salt thereof, wherein each R⁴ is independently H, hydroxyl, halo,C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy,carboxyl, thiol, carbonylalkoxy, thioalkyl, alkylsulfonylamino or acyl.12. The compound of claim 1, or a salt thereof, wherein each R⁴ isindependently nitro, cyano, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, orcarbonylalkylenealkoxy.
 13. The compound of claim 1, or a salt thereof,wherein X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H, and X⁹ is CR⁴ whereR⁴ is substituted or unsubstituted C₁-C₈ alkyl, perhaloalkyl or halo.14. The compound of claim 13, or a salt thereof, wherein X⁹ is CR⁴ whereR⁴ is methyl, CF₃, CH₂F, CHF₂, chloro or fluoro.
 15. The compound ofclaim 1, or a salt thereof, wherein each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, or halo.
 16. The compound of claim 15, or a salt thereof,wherein each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) is H.17. The compound of claim 1, or a salt thereof, wherein Q is asubstituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.
 18. The compound of claim 17, or a salt thereof, wherein Qis selected from the group consisting of:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. 19.The compound of claim 1, or a salt thereof, wherein Q is substituted orunsubstituted pyridyl, substituted or unsubstituted phenyl, substitutedor unsubstituted pyrimidinyl, or substituted or unsubstituted pyrazinyl.20. The compound of claim 1, or a salt thereof, wherein Q isunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl orsubstituted or unsubstituted heterocyclyl.
 21. The compound of claim 20,or a salt thereof, wherein Q is selected from the group consisting of:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino.
 22. The compound of claim 1, or a saltthereof, wherein: at least one of R^(8c), R^(8d), R^(8e) and R^(8f) isC₁-C₈ alkyl; X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; X⁹ is CR⁴ whereR⁴ is substituted or unsubstituted C₁-C₈ alkyl, perhaloalkyl, or halo;and R¹ is substituted or unsubstituted C₁-C₈ alkyl.
 23. The compound ofclaim 1, or a salt thereof, wherein: at least one of R^(8c), R^(8d),R^(8e) and R^(8f) is methyl, ethyl or cyclopropyl; X⁷, X⁸ and X¹⁰ areeach CR⁴ where R⁴ is H; X⁹ is CR⁴ where R⁴ is methyl, CHF₂, CH₂F, CF₃,chloro or fluoro; and R¹ is methyl or cyclopropyl.
 24. The compound ofclaim 1, or a salt thereof, wherein the compound has one or more of thefollowing structural features: R¹ is methyl; Q is a substituted orunsubstituted pyridyl; and X⁹ is CR⁴ where R⁴ is halo, a substituted orunsubstituted C₁-C₈ alkyl, or perhaloalkyl.
 25. The compound of claim 1,or a salt thereof, wherein the compound has one or more of the followingstructural features: R¹ is methyl; Q is a substituted or unsubstitutedphenyl; and X⁹ is CR⁴ where R⁴ is halo, a substituted or unsubstitutedC₁-C₈ alkyl, or perhaloalkyl.
 26. The compound of claim 1, or a saltthereof, wherein: R¹ is methyl or ethyl; each R^(8c), R^(8d), R^(8e) andR^(8f) is independently H or C₁-C₈ alkyl; X⁷ is CR⁴ where R⁴ is H; X⁸and X¹⁰ are independently CR⁴ where R⁴ is H or halo; X⁹ is CR⁴ where R⁴is halo, methyl, trifluoromethyl or ethyl; and Q is a substituted orunsubstituted phenyl or a substituted or unsubstituted pyridyl, providedthat when X⁹ is CR⁴ where R⁴ is halo, then only one of X⁸ and X¹⁰ is CR⁴where R⁴ is halo.
 27. The compound of claim 1, or a salt thereof,wherein: R¹ is unsubstituted C₁-C₈ alkyl; each of R^(2a), R^(2b),R^(3a), R^(3b), R^(10a) and R^(10b) is H; and each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, C₁-C₈ alkyl,carboxy, carbonylalkoxy, or is taken together with the carbon to whichit is attached and a geminal R^(8(a-f)) to form a cycloalkyl moiety. 28.The compound of claim 27, or a salt thereof, wherein—R^(8c)R^(8d)—R^(8e)R^(8f)— and the carbons to which they are attachedare taken together to form a moiety selected from the group consistingof —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—CH₂—, —CH₂—C(CH₃)(CH₃)—, —C(CH₂CH₂)—CH₂—and —CH₂—C(CH₂CH₂)—.
 29. The compound of claim 27, or a salt thereof,wherein Q is a substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.
 30. The compound of claim 1, or a saltthereof, wherein the compound is selected from the group consisting of:No. Structure 113

114

115

116

117

118

122

123

124

125

126

127

131

132

133

134

135

136

381

382

383

384

450

451

455

456

477

478

479

480

521

522

524

525

527

528


31. A compound of the formula (B):

or a salt thereof, wherein: R¹ is H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substitutedor unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl orcarbonylalkylenealkoxy; wherein acyl is selected from the groupconsisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—,alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substitutedalkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—; wherein sulfonylamino is selected from the groupconsisting of —SO₂NH₂, —SO₂NR-alkyl, —SO₂NR-substituted alkyl,—SO₂NR-alkenyl, —SO₂NR-substituted alkenyl, —SO₂NR-alkynyl,—SO₂NR-substituted alkynyl, —SO₂NR-aryl, —SO₂NR-substituted aryl,—SO₂NR-heteroaryl, —SO₂NR-substituted heteroaryl, —SO₂NR-heterocyclic,and —SO₂NR-substituted heterocyclic, where R is H or alkyl, or —SO₂NR₂,wherein the two R groups are taken together and with the nitrogen atomto which they are attached to form a heterocyclic or substitutedheterocyclic ring; wherein sulfonyl is selected from the groupconsisting of —SO₂-alkyl, —SO₂—substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substituted alkynyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, and —SO₂-substituted heterocyclic; eachR^(2a) and R^(2b) is independently H, substituted or unsubstituted C₁-C₈alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acarbonyl moiety; each R^(3a) and R^(3b) is independently H, substitutedor unsubstituted C₁-C₈ alkyl, halo, cyano or nitro or R^(3a) and R^(3b)are taken together with the carbon to which they are attached to form acarbonyl moiety; each X⁷, X⁸, X⁹ and X¹⁰ is CR⁴; each R⁴ isindependently H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl; wherein acyl is selected from the group consisting of H—C(O)—,alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substitutedalkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—,substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—,heterocyclic-C(O)—, and substituted heterocyclic-C(O)—; whereinsulfonylamino is selected from the group consisting of —SO₂NH₂,—SO₂NR-alkyl, —SO₂NR-substituted alkyl, —SO₂NR-alkenyl,—SO₂NR-substituted alkenyl, —SO₂NR-alkynyl, —SO₂NR-substituted alkynyl,—SO₂NR-aryl, —SO₂NR-substituted aryl, —SO₂NR-heteroaryl,—SO₂NR-substituted heteroaryl, —SO₂NR-heterocyclic, and—SO₂NR-substituted heterocyclic, where R is H or alkyl, or —SO₂NR₂,wherein the two R groups are taken together and with the nitrogen atomto which they are attached to form a heterocyclic or substitutedheterocyclic ring; wherein sulfonyl is selected from the groupconsisting of —SO₂-alkyl, —SO₂—substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substituted alkynyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, and —SO₂-substituted heterocyclic; eachR^(8c), R^(8d), R^(8e) and R^(8f) is independently H, C₁-C₈ alkyl, C₁-C₈perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with thecarbon to which it is attached and a geminal R⁸ to form a cycloalkylmoiety, provided that at least one of R^(8c), R^(8d), R^(8e) and R^(8f)is other than H; each R^(10a) and R^(10b) is independently H, halo, asubstituted or unsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a)and R^(10b) are taken together with the carbon to which they areattached to form a carbonyl; and Q is a substituted or unsubstitutedaryl or a substituted or unsubstituted heteroaryl.
 32. The compound ofclaim 31, or a salt thereof, wherein at least one of R^(8e) and R^(8f)is other than H.
 33. The compound of claim 31, or a salt thereof,wherein at least one of R^(8c), R^(8d), R^(8e) and R^(8f) is C₁-C₈alkyl.
 34. The compound of claim 31, or a salt thereof, wherein—R^(8c)R^(8d)—R^(8e)R^(8f)— and the carbons to which they are attachedare taken together to form a moiety selected from the group consistingof —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—CH₂—, —CH₂—C(CH₃)(CH₃)—, —C(CH₂CH₂)—CH₂—and —CH₂—C(CH₂CH₂)—.
 35. The compound of claim 31, or a salt thereof,wherein: R¹ is substituted or unsubstituted C₁-C₈ alkyl; X⁷ is CR⁴ whereR⁴ is H; X⁸ and X¹⁰ are independently CR⁴ where R⁴ is H or halo; X⁹ isCR⁴ where R⁴ is halo, methyl, CHF₂, CH₂F, CF₃, or ethyl; and Q is asubstituted or unsubstituted phenyl or a substituted or unsubstitutedpyridyl, provided that when X⁹ is CR⁴ where R⁴ is halo, then only one ofX⁸ and X¹⁰ is CR⁴ where R⁴ is halo.
 36. The compound of claim 31, or asalt thereof, wherein: R¹ is unsubstituted C₁-C₈ alkyl; each of R^(2a),R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) is H; H and each R^(8c),R^(8d), R^(8e) and R^(8f) is independently H, C₁-C₈ alkyl, or is takentogether with the carbon to which it is attached and a geminalR^(8(c-f)) to form a cycloalkyl moiety.
 37. The compound of claim 31, ora salt thereof, wherein: Q is 3-pyridyl, 4-pyridyl or6-methyl-3-pyridyl; and X⁹ is CR⁴ where R⁴ is chloro, methyl, CHF₂,CH₂F, or CF₃.
 38. The compound of claim 31, or a salt thereof, wherein Qis an unsubstituted 3-pyridyl; X⁹ is CR⁴ where R⁴ is methyl, CHF₂, CH₂For CF₃; and R¹ is methyl.
 39. A pharmaceutical composition comprising acompound according to claim 1, or a salt thereof, and a pharmaceuticallyacceptable carrier.
 40. A kit comprising a compound according to claim1, or a salt thereof, and instructions.
 41. A pharmaceutical compositioncomprising a compound according to claim 31, or a salt thereof, and apharmaceutically acceptable carrier.
 42. A kit comprising a compoundaccording to claim 31, or a salt thereof, and instructions.